Indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ROR gamma (T))

ABSTRACT

Indazole sulfonamide derivatives of formula (I), the pharmaceutically acceptable addition salts thereof, the hydrates and/or solvates thereof, and the use of same as inverse agonists of retinoid-related orphan receptor gamma RORγt are described. Pharmaceutical compositions including such compounds, as well as the use thereof for the topical and/or oral treatment of RORγt receptor-mediated inflammatory diseases, in particular acne, psoriasis and/or atopic dermatitis are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/537,678, filed Jun. 19, 2017, which is the National Stage ofPCT/EP2015/080689, filed Dec. 18, 2015, published on Jun. 23, 2016 as WO2016/097391 A1, which claims priority to French Application No. 1463035,filed Dec. 19, 2014 and to French Application No. 1556341, filed Jul. 3,2015. The contents of these applications are herein incorporated byreference in their entirety.

The present invention relates to particular bicyclic sulfonamidederivatives, to the pharmaceutically acceptable addition salts thereof,hydrates thereof and/or solvates thereof, and also to the use thereof asinverse agonist of the retinoid-related orphan receptor gamma RORγt.

The invention also relates to a pharmaceutical composition comprisingsuch compounds and also to the use thereof for the topical and/or oraltreatment of inflammatory diseases mediated by the RORγt receptors,especially acne, atopic dermatitis and/or psoriasis.

The nuclear receptors form a large family (known as a superfamily) oftranscription factors which correspond to proteins that are capable ofbeing activated by a ligand, of binding to specific DNA sequences and ofregulating the transcription of target genes. Thus, these receptors areinvolved in the regulation of a wide variety of biological functions,including growth, development, reproduction, differentiation andmetabolism in a multitude of living organisms.

The first members of this superfamily that were identified and describedin the scientific literature are the nuclear receptors of steroidhormones such as the glucocorticoid receptors and the estrogenreceptors. This superfamily also comprises among its members manyreceptors for which no ligand has been identified. These nuclearreceptors are known as “orphan receptors”.

Retinoid-related orphan receptors thus constitute a subfamily of nuclearreceptors. This subfamily is composed of three members each having anintrinsic expression profile: ROR alpha (known as RORα), ROR beta (knownas ROM and ROR gamma (known as RORγ). Two isoforms of the orphanreceptors RORγ have already been identified, namely RORγ1, which isexpressed in a variety of tissues such as the thymus, the kidneys,muscles and the liver, and RORγ2 (also known as RORγt), which isexpressed exclusively in the cells of the immune system.

In particular, the receptor RORγt plays an important regulating role incell differentiation of the Th17 lymphocytes which correspond to helperT lymphocytes whose function is to ensure the defence of the bodyagainst a large number of extracellular pathogens such as bacteria andfungal infections.

However, it has been demonstrated that the Th17 lymphocytes are alsoinvolved in a wide variety of inflammatory disorders, such as acne, andof autoimmune diseases such as psoriasis, rheumatoid arthritis ormultiple sclerosis (Peck A, Mellins E D. Precarious balance; Th17 cellsin host defense. Infect. Immun. 2010 January; 78(1): 32-8;Suarez-Farinas: J. Allergy Clin. Immunol. 2014; J. Invest. Dermatol.2008, 128(11), 2625).

Specifically, the Th17 lymphocytes produce numerous cytokines which havedistinct profiles, such as interleukin-17A (IL-17A), interleukin-17F(IL-17F), interleukin-26 (IL-26), interleukin-21 (IL-21), interleukin-22(IL-22) and TNFα, the development, survival and proliferation of whichdepend on interleukin-23 (IL-23). These cytokines are capable ofactivating different types of effector cells, such as keratinocytes,thus leading to their hyperproliferation and to the additionalproduction of pro-inflammatory cytokines, chemokines and antimicrobialpeptides, which in turn recruit and activate other immune system cellsin the inflamed skin, which may lead to amplification of the immuneresponse.

Thus, activation of the Th17 lymphocytes is responsible for therecruitment of cytokines, especially of interleukin-17 (IL17), and ofother types of pro-inflammatory cells, which will lead to the mediationof inflammatory disorders such as acne and/or of autoimmune diseasessuch as psoriasis.

Experiments conducted on mice show that a decrease in the level ofexpression of the RORγt receptor leads to a decrease in the activity ofthe Th17 lymphocytes, which consequently makes it possible to greatlyreduce the expression of interleukin-17 (IL-17) (Ivanov I I, McKenzie BS, Zhou L, Tadokoro C E, Lepelley A, Lafaille J J, Cua D J, Littman D R:Cell 2006, 126, 1121-1133) and to efficiently treat inflammatorydisorders and autoimmune diseases mediated by these cytokines,especially those for which high levels of interleukin-17 (IL-17) aredetected.

To this end, patent application WO 2013/160 418 describes sulfonamidecompounds used as inverse agonists of the RORγt receptor in order to beable to treat inflammatory disorders and autoimmune diseases. Similarly,other compounds have also been developed as inverse agonists of theRORγt receptor, such as those described in patent applications WO2014/090 712, WO 2014/008 214, WO 2013/169 588, WO 2013/160 419, WO2013/1 002 027, WO 2013/092 939, WO 2013/092 941, WO 2013/085 890 and WO2012/100 732.

There is thus a real need to develop novel compounds as inverse agonistsof the RORγt receptor in order to be able to efficiently treat diseasesmediated by such a receptor, especially inflammatory disorders such asacne, and/or autoimmune diseases such as psoriasis or atopic dermatitis.

This aim is achieved by means of the use of particular bicyclicsulfonamide derivatives as described below, which make it possible tomodulate the activity of the RORγt receptor and consequently toefficiently treat inflammatory disorders and autoimmune diseases ofcertain pathologies.

One subject of the present invention is thus especially one or morecompounds of formula (Ia), the pharmaceutically acceptable additionsalts thereof, hydrates thereof and/or solvates thereof:

in which formula (I):

-   -   L represents a single bond or a methylene group CH₂,    -   X represents a cyclic radical chosen from the radicals X₁ and X₂        below:

-   -   one or two of the elements Y¹, Y², Y³, Y⁴ and Y⁵ represent(s) a        nitrogen atom and the other elements correspond to a group —CR²,        or each of the elements Y¹, Y², Y³, Y⁴ and Y⁵ corresponds to a        group —CR²,    -   one or two of the elements Q¹, Q² and Q³ represent(s) a nitrogen        atom and the other element(s) correspond(s) to a group —CR^(2a),        or each of the elements Q¹, Q² and Q³ corresponds to a group        —CR^(2a),    -   R¹ represents a linear or branched C₃-C₅ alkyl radical,        optionally substituted with a hydroxyl group and/or a halogen        atom, a C₃-C₅ cycloalkyl radical, a linear or branched C₂-C₅        alkenyl radical, a (C₁)alkyl(C₃-C₅)cycloalkyl radical, a C₄-C₅        heterocycloalkyl radical, a (C₁)alkyl(C₄-C₆)heterocycloalkyl        radical,    -   R² represents a hydrogen atom or a halogen atom, a linear or        branched C₁-C₅ alkyl radical, a linear or branched C₂-C₄ alkenyl        radical, a C₁-C₄ alkoxy radical, a cyano group —CN, a radical        —C(═O)R′² with R′² denoting a C₁-C₃ alkoxy radical, a —CF₃        radical; said alkyl, alkenyl and alkoxy radicals possibly being        substituted with one or more halogen atoms,    -   R^(2a) represents a hydrogen atom or a halogen atom, a linear or        branched C₁-C₅ alkyl radical, a linear or branched C₂-C₄ alkenyl        radical, a C₁-C₄ alkoxy radical, a —CN group, a hydroxyl group        —OH, a group —CH(R^(3a))OH, a carboxylic group —COOH, a        carbamoyl group —CONR^(2c)R^(2d), an amido group        —NR^(2c)COR^(2d), a group —SO₂R^(2c), a group —SOR^(2c), a group        —S(═O)(═NH—R^(2c)), said alkyl, alkenyl and alkoxy radicals        possibly being substituted with one or more halogen atoms,    -   R^(2c) and R^(2d), which may be identical or different,        represent a hydrogen atom or a linear or branched C₁-C₅ alkyl        radical;    -   R^(3a) represents a hydrogen atom or a linear or branched C₁-C₅        alkyl radical,    -   R³ represents a hydrogen atom, a halogen atom, a group        (CHR⁶)_(n)—(Z)O—(CHR ′⁶)_(p)—R⁷, a group CH═R⁷ or a group        —C═CH—R⁷,    -   n, o and p, which may be identical or different, represent zero        or a natural integer ranging from 1 to 3,    -   —Z represents a divalent group chosen from a methylene group        —CH₂—, an amino group —NH— and an oxygen atom —O—,    -   R⁶ and R′⁶, which may be identical or different, represent a        hydrogen atom, a methyl group —CH₃, a group —OH, a C₁        hydroxyalkyl group, a carboxylic function —COOH,    -   R⁷ represents:    -   a hydrogen atom or a halogen atom,    -   a group COOR′⁷ with R′⁷ denoting (C₁)alkyl(C₆)heterocycle,    -   a non-cationic heterocyclic radical optionally substituted with        one or more halogen atoms, one or more linear or branched C₁-C₃        alkyl groups, one or more —OH groups, one or more carbonyl        functions, one or more linear or branched C₁-C₄ hydroxyalkyl        groups, one or more amino groups, one or more groups        —C(═O)R^(7a), one or more groups S(═O)₂R^(7a); R^(7a)        representing a linear or branched C₁-C₃ alkyl radical, a linear        or branched C₁-C₃ alkoxy radical, or an amino radical        N(R^(8a))(R^(8b)),    -   a non-cationic C₃-C₆ cycloalkyl radical optionally substituted        with one or more C₁ alkyl radicals, one or more halogen atoms, a        cyano group —CN or one or more groups —COR⁹; R⁹ denoting a        linear or branched C₁-C₃ alkoxy radical, or a hydroxyl group,    -   an aromatic or heteroaromatic, non-cationic radical optionally        substituted with one or more halogen atoms, one or more linear        or branched C₁-C₃ alkyl groups optionally substituted with one        or more halogen atoms, one or more C₁-C₃ alkoxy groups, one or        more amino groups —NR¹¹R¹², one or more groups —COR¹¹, one or        more groups —COOR¹¹, one or more amido groups —CONR¹¹R¹², one or        more groups —SOR¹¹, one or more groups —SO₂R¹¹, one or more        groups —NHCOR¹¹, one or more groups —NHCOOR¹¹, one or more        groups —SO₂NR¹¹R¹² or one or more —CN groups; R¹¹ and R¹², which        may be identical or different, representing a hydrogen atom, a        hydroxyl radical —OH, a linear or branched C₁-C₃ alkyl radical        optionally substituted with one or more halogen atoms;    -   when R³ represents a group —CH═R⁷ or a group —C═CH—R⁷, then R⁷        does not represent a hydrogen atom, a halogen atom or a group        COOR′⁷,    -   R⁵ represents a hydrogen atom or a halogen atom, a linear or        branched C₁-C₃ alkyl radical optionally substituted with one or        more halogen atoms; an amino radical —NH₂, a C₄-C₅ heterocyclic        radical, an OCH₂—(C₄-C₅)heterocyclic radical, a radical        CH₂R^(′7a) with R′^(7a) denoting a C₁ alkoxy radical, a hydroxyl        group-OH, a —CH₂COOH group, a group —CH(R^(5b))OH, an amino        group —NH₂, a carboxylic group —COOH, a —CN group, a thioxo        function,    -   R^(5b) represents a hydrogen atom, a linear or branched C₁-C₃        alkyl radical optionally substituted with one or more carboxylic        functions; a cyclopropyl radical,    -   R^(8a) and R^(8b), which may be identical or different, denote a        hydrogen atom, a linear or branched C₁-C₃ alkyl radical or a        cyclopropyl radical.

The compound(s) according to the invention thus correspond to bicyclicsulfonamide derivatives, and thus to one or more sulfonamide compoundsbearing in their structure at least two rings that are fused to eachother.

In other words, X is a cyclic radical fused to the aromatic nucleus,comprising the elements Q¹, Q² and Q³ as defined above.

In accordance with the definition of formula (I), the endocyclic bondbetween the cyclic radical X₁ or X₂, as represented above, and thearomatic nucleus comprising the elements Q₁ to Q₃ is a double bond.Thus, the double bond is common between the cyclic radical X₁ or X₂ andthe aromatic nucleus comprising the elements Q₁ to Q₃.

The compounds according to the invention make it possible to modulate,i.e. to inhibit, the activity of the RORγt receptor.

A subject of the present invention is also the compound(s) as definedpreviously, as medicament and cosmetic.

Another subject of the invention relates to the compound(s) as definedpreviously for their use in the treatment of diseases mediated by theRORγt receptor, especially inflammatory disorders and/or autoimmunediseases mediated by the RORγt receptor.

Moreover, the invention also relates to a pharmaceutical compositioncomprising, in a pharmaceutically acceptable medium, one or morecompounds of formula (I) as defined previously, pharmaceuticallyacceptable addition salts thereof, hydrates thereof and/or solvatesthereof.

The present invention also relates to the pharmaceutical composition asdescribed previously, for its use in the treatment of diseases mediatedby the RORγt receptor, especially inflammatory disorders and/orautoimmune diseases.

Finally, the invention relates to a method for treating diseasesmediated by the RORγt receptor, comprising the administration,especially topically or orally, of a therapeutically effective amount ofone or more compounds as defined above to a patient.

Other subjects, characteristics, aspects and advantages of the inventionwill emerge even more clearly on reading the description and theexamples that follow.

According to one embodiment, in formula (I):

-   -   R³ represents a hydrogen atom, a group        (CHR⁶)_(n)—(Z)_(o)—(CHR¹⁶)_(p)—R⁷, a group CH═R⁷ or a group        —C═CH—R⁷, and    -   R⁵ represents a hydrogen atom or a halogen atom, a linear or        branched C₁-C₃ alkyl radical optionally substituted with one or        more halogen atoms; an amino radical —NH₂, a radical CH₂R′^(7a)        with R′⁷a denoting a C₁ alkoxy radical, a hydroxyl group —OH, a        —CH₂COOH group, a group —CH(R^(5b))OH, an amino group —NH₂, a        carboxylic group —COOH, a —CN group, a thioxo function.

According to one embodiment, in formula (I), L represents a single bond.

According to another embodiment, in formula (I), L represents amethylene group —CH₂.

Preferentially, in formula (I), L represents a single bond.

Preferably:

-   -   when R⁵ is linked to the nitrogen atom, then R⁵ represents a        hydrogen atom or a —CH₂COOH group,    -   when R⁵ is linked to a carbon atom belonging to the cyclic        radical X, then R⁵ represents a hydroxyl group —OH, a group        —CH(R^(5b))OH, an amino group —NH₂, a carboxylic group —COOH, a        halogen atom or a —CN group.

Preferentially, when X═X₁, then R³ is other than a halogen atom and whenX═X₂, then R⁵ represents a hydrogen atom or a linear or branched C₁-C₃alkyl radical optionally substituted with one or more halogen atoms.

More preferentially, R³ and R⁵ are different.

Even more preferentially, R³ represents a hydrogen atom or a group(CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷.

According to one embodiment, R³ represents a hydrogen atom or a group(CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷ and R⁵ represents a hydrogen atom or alinear or branched C₁-C₃ alkyl radical, optionally substituted with oneor more halogen atoms.

Preferably, R¹¹ and R¹² are other than an —OH group.

According to one embodiment, in formula (I), R³ represents a hydrogenatom.

According to one embodiment, in formula (I), R³ represents a group(CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷.

According to one embodiment, in formula (I), the indices n, o and p,which may be identical or different, denote zero.

According to one embodiment, in formula (I), the indices n, o and p,which may be identical or different, denote a natural integer rangingfrom 1 to 3.

According to one embodiment, in formula (I), the indices n and p denotezero and the index o is equal to 1.

According to one embodiment, in formula (I), Z represents a methylenegroup —CH₂.

According to one embodiment, in formula (I), Z represents a divalentgroup-O—.

According to one embodiment, in formula (I), Z represents a divalentgroup-NH—.

According to one embodiment, in formula (I), R³ represents a group Z—R⁷,with Z having the meaning described previously.

According to a particular embodiment, in formula (I), R³ represents agroup-CH₂—R⁷.

According to a particular embodiment, in formula (I), R³ represents agroup-O—R⁷.

According to a particular embodiment, in formula (I), R³ represents agroup-NH—R⁷.

According to one embodiment, in formula (I), R⁷ represents aheterocyclic radical chosen from the following heterocycles:

in which:

-   -   R_(7a) represents a linear or branched C₁-C₃ alkyl radical, a        linear or branched C₁-C₃ alkoxy radical or an amino radical        N(R^(8a))(R^(8b)),    -   R^(8a) and R^(8b), which may be identical or different, denote a        hydrogen atom, a linear or branched C₁-C₃ alkyl radical or a        cyclopropyl radical,    -   R₈ and R₉, which may be identical or different, represent a        hydrogen atom, a linear or branched C₁-C₃ alkyl radical, a        hydroxyl group —OH, a carbonyl function ═O, a C₁ hydroxyalkyl        radical (—CH₂OH), an amino group NH₂,    -   R₈ and R₉ can form, together with the carbon atoms to which they        are attached, a 5- to 7-membered carbocyclic ring.

According to one embodiment, in formula (I), R⁷ represents an aromaticor heteroaromatic radical chosen from:

in which:

-   -   R₁₀ represents a hydrogen atom or a halogen atom, one linear or        branched C₁-C₃ alkyl group optionally substituted with one or        more halogen atoms, one C₁-C₃ alkoxy group, one amino group        —NR¹¹R¹², one group —COR¹¹, one group —COOR¹¹, one amido group        —CONR¹¹R¹², one group —SOR¹¹, one group —SO₂R¹¹, one group        —NHCOR¹¹, one group —NHCOOR¹¹, one group —SO₂R¹¹R¹² or one —CN        group; R¹¹ and R¹², which may be identical or different,        representing a hydrogen atom or a linear or branched C₁-C₃ alkyl        radical optionally substituted with one or more halogen atoms,    -   m denotes zero or a natural integer ranging from 1 to 3.

Preferably, R¹¹ and R¹² are other than an —OH group.

Preferentially, R⁷ represents an aromatic or heteroaromatic radical asdefined previously, optionally substituted with one or more methylgroups —CH₃, one or more methoxy groups —OCH₃, one or more hydroxylgroups —OH, one or more amino groups —NH₂, one or more —CH₂OH groups,one or more cyano groups —CN, one or more halogen atoms or one or morecarbonyl functions.

According to one embodiment, the index m is equal to zero.

According to one embodiment, the index m denotes a natural integerranging from 1 to 3.

Preferentially, the index m is equal to 1.

According to one embodiment, in formula (I), each of the elements Y¹,Y², Y³, Y⁴ and Y⁵ corresponds to a group —CR² with R² having the samemeaning as that described previously.

According to one embodiment, in formula (I), each of the elements Y¹,Y², Y³, Y⁴ and Y⁵ corresponds to a group —CR² with R² representing ahydrogen atom.

According to one embodiment, in formula (I), each of the elements Y¹,Y², Y³, Y⁴ and Y⁵ corresponds to a group —CR² with R² representing alinear or branched C₁-C₅ alkyl radical.

According to one embodiment, in formula (I), each of the elements Q¹, Q²and Q³ represents a group —CR^(2a) with R^(2a) having the same meaningas that described previously.

According to one embodiment, in formula (I), each of the elements Q¹, Q²and Q³ represents a group —CR^(2a) with R^(2a) representing a hydrogenatom.

According to one embodiment, in formula (I), Q¹ and Q² represent a group—CR^(2a) with R^(2a) representing a hydrogen atom and Q³ represents agroup —CR^(2a) with R^(2a) representing a linear or branched C₁-C₅ alkylradical.

According to one embodiment, in formula (I), IV represents a linear orbranched C₃-C₅ alkyl radical, preferably a branched C₃-C₅ and morepreferentially branched C₄ alkyl radical.

According to one embodiment, in formula (I), IV represents a C₃-C₅cycloalkyl radical, preferably cyclopropyl.

According to one embodiment, in formula (I), R¹ represents a linear orbranched C₂-C₅ alkenyl radical.

According to one embodiment, in formula (I), R¹ represents aCH₂—(C₃-C₅)cycloalkyl radical.

According to one embodiment, in formula (I), R¹ represents a C₄-C₅heterocycloalkyl radical.

According to one embodiment, in formula (I), R¹ represents aCH₂—(C₄-C₆)heterocycloalkyl radical, in particular aCH₂—(C₄-C₅)heterocycloalkyl radical.

Preferentially, R¹ represents a linear or branched C₃-C₅ alkyl radical,or a CH₂—(C₄-C₅)heterocycloalkyl radical.

According to one embodiment, R⁵ represents a hydrogen atom.

Preferably, the compound(s) of formula (I) are chosen from thecompound(s) of formula (II), the pharmaceutically acceptable additionsalts thereof, hydrates thereof and/or solvates thereof:

in which formula (II) R¹, R³, R⁵ and Y¹ to Y⁵ have the same meanings asin formula (I) described previously.

Preferentially, R³ represents a group (CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷with R⁶, Z, R′⁶, R⁷ and the indices n, o and p having the same meaningsas those indicated previously.

More preferentially, R³ represents a group CH₂—R⁷ with R⁷ representing anon-cationic heterocyclic radical.

Preferably, the compound(s) of formula (I) are chosen from thecompound(s) of formula (III), the pharmaceutically acceptable additionsalts thereof, hydrates thereof and/or solvates thereof:

in which formula (III) R¹, R³, R⁵ and Y¹ to Y⁵ have the same meanings asin formula (I) described previously.

Preferentially, in formula (III), R₅ represents a hydrogen atom or alinear or branched C₁-C₃ alkyl radical optionally substituted with oneor more halogen atoms.

The compounds of formula (I) may be in the form of pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable salts aredescribed in Berge et al., 1977, “Sels pharmaceutiquement acceptables”[Pharmaceutically acceptable salts], J. Pharm. Sci., Vol. 66, pages1-19.

In particular, when the compounds of formula (I) according to theinvention are in the form of salts, then the electrical neutrality ofsaid compounds is ensured by an external cationic counterion Y which maybe organic or mineral.

Y may be chosen from suitable inorganic cations such as alkali metalions, especially Na⁺, K⁺, alkaline-earth metal ions, especially Ca²⁺,Mg²⁺, or alternatively other cations such as the aluminum ion Al³⁺.

Y may be chosen from suitable organic cations such as the ammonium ionNH₄+, substituted ammonium ions such as NH₃R⁺, NHR₂ ⁺, NR₄ ⁺ with Rrepresenting a C₁-C₄ alkyl radical.

In particular, the substituted ammonium ions are those chosen fromderivatives of ethylamine, diethylamine, dicyclohexylamine,triethylamine, butylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline,meglumine and tromethamine, and amino acids such as lysine and arginine.

An example of a quaternary ammonium ion may be the ion N⁺ (CH₃)₄.

The compound(s) according to the invention may be in the form of thesolvates thereof.

For the purposes of the present invention, the term “solvate” means acomplex of solute (i.e. the compound according to the invention or thesalt of said compound) and of solvent.

If the solvent is water, then the solvate may suitably be considered asa hydrate, for example, a hemihydrate, a monohydrate, a dihydrate, atrihydrate, etc.

For example, the solvates and/or hydrates may be obtained directly atthe end of the synthetic process, the target compound being isolated inthe form of a hydrate, for example a monohydrate or hemihydrate, or inthe form of a solvate of the reaction solvent and/or purificationsolvent.

Unless otherwise indicated, any reference to a compound according to theinvention also includes the solvate or the hydrate of the correspondingcompound.

Typical processes for the preparation and identification of hydrates andsolvates are well known to those skilled in the art: see, for example,pages 202-209 of K J Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids” in Polymorphism in PharmaceuticalSolids, edition. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., NewYork, 1999.

The hydrates and solvates may be isolated and characterized via methodsknown in the art, such as thermogravimetric analysis (TGA), TGA-massspectroscopy, TGA-infrared spectroscopy, x-ray powder diffraction, KarlFischer titration, high-resolution x-ray diffraction, and the like.

Preferably, the compound(s) of formula (Ia) are chosen from thecompounds as described in the tables below, and also thepharmaceutically acceptable addition salts thereof, hydrates thereofand/or solvates thereof:

TABLE 1 IC50 IC50 hRORg hCD4/IL17

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid(4-ethylphenyl)(1- ethylpropyl)amide Compound 1 B B

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid((R)-sec-butyl)(4- ethylphenyl)amide Compound 2 B ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acidcyclopropyl(4- ethylphenyl)amide Compound 3 C ND

3-bromo-1- (tetrahydropyran-2- yl)-1H-indazole-6- sulfonic acid (4-ethylphenyl) isobutylamide Compound 4 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(tetrahy- dropyran-4- ylmethyl)amide Compound 5 C ND

1-((3,5- dimethylisoxazol-4- yl)methyl)-N-(4- ethylphenyl)-N-isobutyl-1H-indazole- 5-sulfonamide Compound 6 B ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-isopropylphenyl)amide Compound 7 B ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)propyl Compound 8 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-ethylphenyl)amide Compound 9 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid(5-chloro-2- fluorophenyl) isobutylamide Compound 10 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (2,5-dimethylphenyl) isobutylamide Compound 11 B ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (3-methoxypyridin-2- yl)isobutylamide Compound 12 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-butyl-2-methylphenyl) isobutylamide Compound 13 B ND

N-(4-ethylphenyl)-N- isobutyl-1- ((tetrahydro-2H-pyran- 4-yl)methyl)-1H-indazole-5- sulfonamide Compound 14 C ND

3-amino-1H-indazole- 5-sulfonic acid (4- ethylphenyl) isobutylamideCompound 15 C ND

1-(tetrahydropyran-4- ylmethyl)-lH- indazole-5-sulfonic acid (4-ethylphenyl)oxetan-3- ylmethylamide Compound 16 C ND

1-(1-acetylpyrrolidin- 3-yl)-1H-indazole-5- sulfonic acid (4-ethylphenyl) isobutylamide Compound 17 B ND

3-(tetrahydropyran-4- ylmethoxy)-1- (tetrahydropyran-4- ylmethyl)-1H-indazole-5-sulfonic acid (4- ethylphenyl) isobutylamide Compound 18 C ND

1-(3,5- dimethylisoxazol-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl) isobutylamide Compound 19 C ND

1-((1-acetylpyrrolidin- 3-yl)methyl)-N-(4- ethylphenyl)-N-isobutyl-1H-indazole- 5-sulfonamide Compound 20 C ND

N-(4-ethylphenyl)-N- isobutyl-1- ((tetrahydrofuran-3- yl)methyl)-1H-indazole-5- sulfonamide Compound 21 C ND

N-(4-ethylphenyl)-N- isobutyl-1- ((tetrahydro-2H-pyran- 3-yl)methyl)-1H-indazole-5- sulfonamide Compound 22 C ND

1-benzyl-N-(4- ethylphenyl)-N- isobutyl-1H-indazole- 5-sulfonamideCompound 23 C ND

N-(cyclobutylmethyl)- N-(4-ethylphenyl)-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H- indazole-5- sulfonamide Compound 24 B ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (3-methoxyphenyl) isobutylamide Compound 25 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (3-methylphenyl) isobutylamide Compound 26 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (2,4-dimethylphenyl) isobutylamide Compound 27 B ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (3,5-dimethylphenyl) isobutylamide Compound 28 C ND

N-(4-ethylphenyl)-N- isopropyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H- indazole-5- sulfonamide Compound 29 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acidsec-butyl(4- ethylphenyl)amide Compound 30 B ND

N- (cyclopropylmethyl)- N-(4-ethylphenyl)-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H- indazole-5- sulfonamide Compound 31 C ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acidcyclopentyl(4- ethylphenyl)amide Compound 32 A ND

1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(tetrahy- drofuran-3- ylmethyl)amide Compound 33 C ND

3-amino-1H-indazole- 5-sulfonic acid (4- ethylphenyl) isobutylamideCompound 34 C ND

N-(4-ethylphenyl)-N- isopentyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H- indazole-5- sulfonamide Compound 35 C ND

N-(4-ethylphenyl)-N- isobutyl-1-(pyridin-4- ylmethyl)-1H- indazole-5-sulfonamide Compound 36 B A

N-(4-ethylphenyl)-N- isobutyl-1-(oxetan-3- ylmethyl)-1H- indazole-5-sulfonamide Compound 37 B A

1-(tetrahydropyran-4- yl)-1H-indazole-5- sulfonic acid (4- ethylphenyl)isobutylamide Compound 38 C ND

N-(4-ethylphenyl)-N- isobutyl-1- ((tetrahydro-2H-pyran- 4-yl)methyl)-1H-indazole-5- sulfonamide Compound 39 B B

TABLE 2 IC50 IC50 hRORg hCD4/IL17

1-(1-acetylpyrrolidin-3-yl)- 1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 40 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acidcyclobutyl(4- ethylphenyl)amide Compound 41 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid(5-fluoro-2- methylphenyl)isobutylamide Compound 42 B ND

1-(tetrahydropyran-4- ylmethyl)-2H-indazole-5- sulfonic acid(3-fluoro-2- methylphenyl)isobutylamide Compound 43 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (5-chlorophenyl)isobutylamide Compound 44 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (2-chlorophenyl)isobutylamide Compound 45 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (4-fluorophenyl)isobutylamide Compound 46 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl-p-tolylamide Compound 47 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl-o-tolylamide Compound 48 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (4-trifluoromethoxyphenyl) isobutylamide Compound 49 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl(5-isopropylpyridin-2-yl)amide Compound 50 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (3-chlorobenzyl)isobutylamide Compound 51 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl(2-trifluoromethylbenzyl)amide Compound 52 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid(2-fluoro-6- methylphenyl)isobutylamide Compound 53 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid(4-fluoro-2- methylphenyl)isobutylamide Compound 54 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl(4-methoxy-2- methylphenyl)amide Compound 55 B ND

methyl 4-{isobutyl[1- (tetrahydropyran-4- ylmethyl)-1H-indazole-5-sulfonyl]amino}-3- methylbenzoate Compound 56 B A

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (4-cyano-2-methylphenyl)isobutylamide Compound 57 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl(2-trifluoromethylphenyl)amide Compound 58 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl(4-trifluoromethylphenyl)amide Compound 59 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid(3-chloro-2- hydroxymethylpropyl)(4- ethylphenyl)amide Compound 60 C ND

3-(tetrahydropyran-4- ylmethoxy)-1H-indazole-5- sulfonic acid (4-ethylphenyl)isobutylamide Compound 61 C ND

3-(tetrahydropyran-4- ylidenemethyl)-1H- indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 62 A ND

3-(tetrahydropyran-4- ylmethyl)-1H-indazole-6- sulfonic acid (4-ethylphenyl)isobutylamide Compound 63 A A

3-morpholin-4-ylmethyl- 1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 64 A A

3-((cis)-2,6- dimethylmorpholin-4- ylmethyl)-1H-indazole-6- sulfonicacid (4- ethylphenyl)isobutylamide Compound 65 C ND

3-((S)-3-methylmorpholin- 4-ylmethyl)-1H-indazole-6- sulfonic acid (4-ethylphenyl)isobutylamide Compound 66 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid isobutyl-o-tolylamide Compound 69 C ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (2-cyano-4-methylphenyl)isobutylamide Compound 70 B ND

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (4,6-dimethylpyridin-3- yl)isobutylamide Compound 71 C C

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (4-dimethylaminophenyl) isobutylamide Compound 72 B B

1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid(2-fluoro-4- methylphenyl)isobutylamide Compound 73 ND ND

methyl 5-[(4- ethylphenyl)isobutyl- sulfamoyl]-1- (tetrahydropyran-4-ylmethyl)-1H-indazole- 7-carboxylate Compound 74 C ND

5-[(4- ethylphenyl)isobutyl- sulfamoyl]-1- (tetrahydropyran-4-ylmethyl)-1H-indazole- 7-carboxylic acid amide Compound 75 ND ND ND: notdetermined; A: IC50 <100 nM.; B: IC50 = 100 nM-1 μM; C: IC50 >1 μM

In the tables described above, the median inhibitory concentrations IC₅₀for the compounds belonging to formula (I) according to the inventionhave been given according to the following models:

GAL4-RORγ Transactivation

The RORγ transactivation model was developed from the line HG5LN, whichis a HeLa line that stably expresses a luciferase reporter genecontrolled by a pentamer of the GAL4 recognition domain of yeast and ofa β-globin promoter. The HG5LN line was stably transfected by theDNA-binding domain (DBD) of GAL4 fused to the ROR gamma ligand-bindingdomain (LBD). Molecules that inhibit the ROR gamma constitutive activityreduce the luciferase expression, thus leading to a reduction in theemitted luminescence.

The cells are seeded in 384-well plates (5000 cells in 45 μL/well ofculture medium containing 10% fetal calf serum) and incubated for 4hours at 37° C., 5% CO₂. 5 μL of the test molecules (compounds describedin the tables described above) are then added to each well and theplates are incubated for 18 hours at a temperature of 37° C. under 5% ofCO₂. 20 μL of luciferase substrate (Promega) are added to each well andthe luminescence emitted is read by a microplate reader.

The luminescence units (“RLU”) are normalized by positive controls(“POS” containing a saturated concentration ofN-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl])benzenesulfonamideand negative controls (“NEG” containing DMSO): %inhibition=((RLU−NEG)*100)/(POS−NEG). The IC50 values are calculatedfrom a 4-parameter logistic model using the XLFit software (IDBS).

IL-17A Secretion

This model allows measurement of the effect of inhibitors on IL-17Asecretion by CD4+ cells. The cells are frozen CD4+ cells (STEMCELL,#70026), isolated from peripheral human blood and activated withanti-CD3 and anti-CD28 antibodies. The amount of IL-17a secreted ismeasured by the TR-FRET (kit HTRF® Human Interleukin 17A (Cisbio,#64H17PEC)) technology.

The cells are rapidly thawed, resuspended in their culture medium (RPMIinactivated 10% FCS) supplemented with soluble anti-CD28 antibodies andseeded (100 000 cells/well) in 96-well plates precoated with anti-CD3antibodies. The cells are then treated with the ranges of inhibitors tobe tested (from 1000 nM to 0.05 nM, 0.1% DMSO). After 4 days ofincubation, the HTRF signal is measured using a microplate reader(λexcitation=337 nm, λemission=620/665 nm). The ratios obtained(665/620) are normalized relative to the positive control (cellsactivated with anti-CD3 and anti-CD28, 0.1% DMSO). The IC₅₀ values arecalculated from a 4-parameter logistic model using the XLFit software(IDBS).

Preferentially, the compounds of formula (I) according to the inventionare chosen from the following compounds:

TABLE 3

N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide Compound 39

N-(4-ethylphenyl)-N-isobutyl-1- (oxetan-3-ylmethyl)-1H-indazole-5-sulfonamide Compound 37

1-((1-acetylpyrrolidin-3-yl)methyl)-N- (4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide Compound 20

1-((3,5-dimethylisoxazol-4-yl)methyl)- N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide Compound 24

1-(1-acetylpyrrolidin-3-yl)-1H-indazole- 5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 40

N-(cyclobutylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide Compound 24

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acidcyclopentyl(4- ethylphenyl)amide Compound 32

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid sec-butyl(4-ethylphenyl)amide Compound 30

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(1-ethylpropyl)amide Compound 1

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-isopropylphenyl)amide Compound 7

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-fluoro-2-methylphenyl)isobutylamide Compound 42

1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid (3-fluoro-2-methylphenyl)isobutylamide Compound 43

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5-dimethylphenyl)isobutylamide Compound 11

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-butyl-2-methylphenyl)isobutylamide Compound 13

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4-dimethylphenyl)isobutylamide Compound 27

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(2-trifluoromethylbenzyl)amide Compound 52

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-fluoro-2-methylphenyl)isobutylamide Compound 54

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(4-methoxy-2-methylphenyl)amide Compound 55

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-cyano-2-methylphenyl)isobutylamide Compound 57

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(2-trifluoromethylphenyl)amide Compound 58

3-(tetrahydropyran-4-ylmethyl)-1H- indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 63

3-morpholin-4-ylmethyl-1H-indazole-6- sulfonic acid (4-ethylphenyl)isobutylamide Compound 64

3-((S)-3-methylmorpholin-4-ylmethyl)- 1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 66

In particular, among the compounds of formula (II), compounds 1, 2, 7,11, 21, 24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57 and 58are preferred.

Among the compounds of formula (III), compounds 63, 64 and 66 arepreferred.

The invention also relates to the compound(s) as described previously,as medicament and cosmetic.

Preferably, the invention also relates to the compound(s) as describedpreviously, as medicament.

Specifically, the compounds according to the invention have advantageouspharmacological properties, given that said compounds modulate, i.e.inhibit, the activity of the RORγt receptor.

Thus, these properties make the compound(s) of formula (I) as describedpreviously usable as medicament in the treatment of diseases mediated bythe RORγt receptor.

Preferably, the compound(s) according to the invention are used in thetreatment of inflammatory disorders and/or autoimmune diseases mediatedby the RORγt receptor.

More preferentially, the compound(s) according to the invention,preferably those chosen from the compounds corresponding to formulae(II) and (III), are used in the treatment of acne, psoriasis and/oratopic dermatitis.

According to another embodiment, the compounds according to theinvention are used for cosmetic treatment of the skin.

As indicated above, the present invention also relates to apharmaceutical composition comprising, in a pharmaceutically acceptablemedium, one or more compounds of formula (I) as defined previously,pharmaceutically acceptable addition salts thereof, hydrates thereofand/or solvates thereof.

Preferably, the pharmaceutical composition comprises one or morecompounds chosen from the compounds of formulae (II) and (III) asdefined previously, the pharmaceutically acceptable addition saltsthereof, hydrates thereof and/or solvates thereof.

More preferentially, the pharmaceutical composition comprises one ormore compounds of formula (I) chosen from compounds (1) to (75) definedpreviously.

Even more preferentially, the pharmaceutical composition comprises oneor more compounds of formula (I) chosen from compounds 1, 2, 7, 11, 21,24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57, 58, 63, 64 and66.

The pharmaceutical composition according to the invention as describedpreviously may be administered orally or topically.

Preferably, the pharmaceutical composition is conditioned in a form thatis suitable for topical application.

Via the oral route, the composition may be in the form of tablets, gelcapsules, coated tablets, syrups, suspensions, solutions, powders,granules, emulsions, suspensions of microspheres or nanospheres or lipidor polymeric vesicles allowing controlled release.

Via the topical route, the pharmaceutical composition according to theinvention is more particularly intended for treating the skin and mucousmembranes, and may be in liquid, pasty or solid form, and moreparticularly in the form of ointments, creams, milks, pomades, powders,impregnated pads, syndets, solutions, gels, sprays, mousses,suspensions, sticks, shampoos or washing bases. It may also be in theform of suspensions of microspheres or nanospheres or lipid or polymericvesicles or of polymeric or gelled patches allowing controlled release.

The pharmaceutical composition is used for treating inflammatorydisorders and/or autoimmune diseases mediated by the RORγt receptor.

More preferentially, the pharmaceutical composition is used in thetreatment of acne and/or psoriasis.

The invention also relates to a process for treating diseases mediatedby the RORγt receptor, comprising the administration, especiallytopically or orally, of a therapeutically effective amount of thepharmaceutical composition as defined above to a patient.

Preferably, the pharmaceutical composition is applied topically.

In accordance with another embodiment, a subject of the presentinvention is also one or more compounds of formula (II) as definedpreviously, the pharmaceutically acceptable addition salts thereof,hydrates thereof and/or solvates thereof:

in which formula (II) R¹, R³, R⁵ and Y¹ to Y⁵ have the same meanings asin formula (Ia) described previously.

Preferably, R³ represents a group (CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷ withR⁷ representing a non-cationic heterocyclic radical, a non-cationiccycloalkyl radical or a non-cationic aromatic or heteroaromatic radicalas defined previously.

Among the compounds of formula (II), compounds 1, 2, 7, 11, 21, 24, 27,30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57 and 58 are preferred.

According to this embodiment, the invention also relates to thecompound(s) of formula (II), as medicament and cosmetic.

In particular, the invention relates to the compound(s) of formula (II),for their use in the treatment of inflammatory disorders and/orautoimmune diseases mediated by the RORγt receptor.

Preferentially, a subject of the invention is the compound(s) of formula(II) for their use in the treatment of acne.

As a variant, a subject of the invention is also the compound(s) offormula (II) for their use in the treatment of psoriasis.

Alternatively, the compound(s) of formula (II) according to theinvention are used for cosmetic treatment of the skin.

Furthermore, the invention also relates to a pharmaceutical compositioncomprising, in a pharmaceutically acceptable medium, one or morecompounds of formula (II) as defined previously, pharmaceuticallyacceptable addition salts thereof, hydrates thereof and/or solvatesthereof.

The pharmaceutical composition is used for treating inflammatorydisorders and/or autoimmune diseases mediated by the RORγt receptor.

In accordance with another embodiment, a subject of the presentinvention is also one or more compounds of formula (III) as definedpreviously, the pharmaceutically acceptable addition salts thereof,hydrates thereof and/or solvates thereof:

in which formula (III) R¹, R³, R⁵ and Y¹ to Y⁵ have the same meanings asin formula (I) described previously.

Preferably, R³ represents a group (CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷ withR⁷ representing a non-cationic heterocyclic radical, a non-cationiccycloalkyl radical or a non-cationic aromatic or heteroaromatic radicalas defined previously.

Among the compounds of formula (III), compounds 63, 64 and 66 arepreferred.

According to this embodiment, the invention also relates to thecompound(s) of formula (III), as medicament and cosmetic.

In particular, the invention relates to the compound(s) of formula(III), for their use in the treatment of inflammatory disorders and/orautoimmune diseases mediated by the RORγt receptor.

Preferentially, a subject of the invention is the compound(s) of formula(III) for their use in the treatment of acne.

As a variant, a subject of the invention is also the compound(s) offormula (III) for their use in the treatment of psoriasis.

Alternatively, the compound(s) of formula (III) according to theinvention are used for cosmetic treatment of the skin.

Furthermore, the invention also relates to a pharmaceutical compositioncomprising, in a pharmaceutically acceptable medium, one or morecompounds of formula (III) as defined previously, pharmaceuticallyacceptable addition salts thereof, hydrates thereof and/or solvatesthereof.

The pharmaceutical composition is used for treating inflammatorydisorders and/or autoimmune diseases mediated by the RORγt receptor.

The examples that follow serve to illustrate the invention without,however, being limiting in nature.

EXAMPLES

The standard LCMS method for analyzing the products is as follows: BEHC₁₈ standard column (150×2.1 mm, 1.8 μm) solvent: water/acetonitrile0.1% formic acid.

The preparative HPLC purifications were performed on a C₁₈ column using,as eluent: 85% acetonitrile in water/0.1% formic acid.

Part I: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 1

Example 1: Synthesis ofN-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide

1. Synthesis of Intermediate 1.1

(4-ethylphenyl)isobutylamine

Isobutyraldehyde (6.33 ml; 0.07 mol) in tetrahydrofuran (100 ml) isadded to 4-ethylaniline (9.48 ml; 0.08 mol). The mixture is stirred for2 hours at room temperature. Sodium triacetoxyborohydride (22.04 g; 0.10mol) is then added. The mixture is stirred overnight at roomtemperature, water (100 ml) are added and the resulting mixture isextracted with ethyl acetate (2×100 ml). The organic phases arecombined, washed with brine (100 ml), dried (Na₂SO₄) and concentrated.

The crude product is chromatographed on silica gel (eluent:heptane/dichloromethane from 0 to 50% of dichloromethane). The(4-ethylphenyl)isobutylamine is obtained in the form of an orange oilwith a compliant ¹H NMR.

MS: [M+H]=179

2. Synthesis of Intermediate 1.2

N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide

1H-Indazole-5-sulfonyl chloride (502 mg; 2.20 mmol) is added to(4-ethylphenyl)isobutylamine (300 mg; 1.69 mmol) and pyridine (820 μl;10.15 mmol) in tetrahydrofuran (6 ml). The reaction medium is stirredfor 7 hours at room temperature, hydrolyzed and extracted with ethylacetate. The organic phases are combined, washed with brine, dried(Na₂SO₄) and concentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 20 to 50% of ethyl acetate). TheN-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (357 mg; 59%) isobtained in the form of a cream-colored solid with a compliant ¹H NMR.

MS: [M+H]=358

3. Synthesis of Compound 39 According to the Invention

4-(Bromomethyl)tetrahydropyran (90 mg; 0.50 mmol) is added toN-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (150 mg; 0.42mmol) and cesium carbonate (137 mg; 0.42 mmol) in N,N-dimethylformamide(12 ml). The reaction medium is stirred for 30 minutes at a temperatureof 100° C. under microwave irradiation, hydrolyzed and extracted withethyl acetate. The organic phases are combined, washed with brine, dried(Na₂SO₄) and concentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, 40% of ethyl acetate). TheN-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide(97 mg; 50%) is obtained in the form of a white powder.

¹H NMR (400 MHz, DMSO-d6) δ 0.85 (d, J=6.6 Hz, 7H), 1.17 (t, J=7.6 Hz,4H), 1.22-1.53 (m, 6H), 2.16-2.31 (m, 1H), 2.59 (q, J=7.6 Hz, 2H),3.15-3.44 (m, 6H), 3.83 (ddd, J=11.5, 4.4, 2.0 Hz, 3H), 4.39 (d, J=7.2Hz, 3H), 6.92-7.05 (m, 3H), 7.10-7.21 (m, 3H), 7.26 (dd, J=9.1, 1.8 Hz,1H), 7.74 (d, J=9.3 Hz, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.62 (s, 1H).

MS: [M+H]=456

With a procedure similar to that described for the synthesis of example1, the compounds of the table below are obtained:

Example 2

N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydro-2H-pyran-3-yl)methyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H),1.17 (t, J = 7.6 Hz, 3H), 1.23-1.35 (m, 1H), 1.35-1.53 (m, 2H),1.54-1.72 (m, 2H), 2.08-2.23 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 3.21(dd, J = 11.2, 8.9 Hz, 1H), 3.32- 3.40 (m, 3H), 3.57-3.65 (m, 1H), 3.70(dt, J = 10.9, 3.9 Hz, 1H), 4.31-4.48 (m, 2H), 6.96 (d, J = 8.3 Hz, 2H),7.16 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 9.0, 1.8 Hz, 1H), 7.84- 7.89 (m,1H), 8.09 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 0.8 Hz, 1H) MS: [M + H] =456 Example 3

N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydrofuran-3-yl)methyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 6H),1.17 (t, J = 7.6 Hz, 3H), 1.42 (hept, J = 6.8 Hz, 1H), 1.57-1.73 (m,1H), 1.83-2.00 (m. 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.81 (hept, J = 7.1Hz, 1H), 3.31-3.35 (m, 2H), 3.50 (dd, J = 8.6, 5.6 Hz, 1H), 3.60-3.71(m, 2H), 3.81 (td, J = 8.1, 5.5 Hz, 1H), 4.36- 4.55 (m, 2H), 6.96 (d, J= 8.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 8.8, 1.8 Hz, 1H),7.90 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 0.9 Hz,1H) MS: [M + H] = 442 Example 4

N-(4-ethylphenyl)-N-isobutyl-1-(oxetan-3-ylmethyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.41 (non, J = 6.8 Hz, 1H), 2.60 (q,J = 7.6 Hz, 2H), 3.32 (m, 2H), 3.52 (tt, J = 7.6, 6.1 Hz, 1H), 4.49 (t,J = 6.2 Hz, 2H), 4.67 (dd, J = 7.8, 6.1 Hz, 2H), 4.77 (d, J = 7.2 Hz,2H), 6.96 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.47 (dd, J =8.9, 1.7 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H),8.29 (d, J = 0.9 Hz, 1H) MS: [M + H] = 428 Example 5

1-((1-acetylpyrrolidin-3-yl)methyl)-N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5- sulfonamide 1H NMR (DMSO-d6, 80°C.) δ: 0.86 (d, J = 6.6 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.44- 1.60(m, 1H), 1.60-1.83 (m, 1H), 1.83- 2.07 (m, 4H), 2.61 (q, J = 7.6 Hz,2H), 2.72- 2.94 (m, 1H), 3.09-3.61 (m, 6H), 4.51 (d, J = 7.1 Hz, 2H),6.99 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.7 Hz,1H), 7.85 (d, J = 8.9 Hz, 1H), 8.10 (s, 1H), 8.28 (s, 1H) MS: [M + H] =483 Example 6

1-benzyl-N-(4-ethylphenyl)-N-isobutyl-1H- indazole-5-sulfonamide 1H NMR(DMSO-d6) δ: 0.84 (d, J = 6.7 Hz, 6H), 1.16 (t, J = 7.6 Hz, 3H), 1.41(hept, J = 6.9 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H), 3.32 (m, 2H), 5.71 (s,2H), 6.98 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.25 (dd, J =9.2, 1.8 Hz, 1H), 7.31-7.43 (m, 5H), 7.73 (d, J = 9.1 Hz, 1H), 8.12 (dd,J = 1.9, 0.8 Hz, 1H), 8.75 (d, J = 1.0 Hz, 1H) MS: [M + H] = 448 Example7

N-(4-ethylphenyl)-N-isobutyl-1-(pyridin-4-ylmethyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.32-1.48 (m, 1H), 2.59 (q, J = 7.7Hz, 2H), 3.33 (m, 2H), 5.82 (s, 2H), 6.96 (d, J = 7.9 Hz, 2H), 7.15 (dd,J = 11.8, 6.5 Hz, 4H), 7.48 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 8.9 Hz,1H), 8.14 (s, 1H), 8.39 (s, 1H), 8.52 (d, J = 5.1 Hz, 2H) MS: [M + H] =449 Example 8

1-((3,5-dimethylisoxazol-4-yl)methyl)-N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5- sulfonamide 1H NMR (DMSO-d6)δ: 0.85 (d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.41 (hept, J =6.8 Hz, 1H), 2.11 (s, 3H), 2.44 (s, 3H), 2.59 (q, J = 7.6 Hz, 2H), 3.33(s, 2H), 5.54 (s, 2H), 6.88-7.00 (m, 2H), 7.12-7.20 (m, 2H), 7.50 (dd, J= 8.9, 1.8 Hz, 1H), 7.88-8.01 (m, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.30(d, J = 0.9 Hz, 1H) MS: [M + H] = 467

Example 9: Synthesis of1-((1-acetylazetidin-3-yl)methyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide

1-(3-Hydroxymethylazetidin-1-yl)ethanone (0.27 g; 2.09 mmol) in toluene(1 ml) is added to a mixture ofN-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (0.20 g; 0.56mmol) and (triphenyl-λ⁵-phosphanylidene)acetonitrile (0.51 g; 1.68 mmol)in anhydrous toluene (3 ml) under argon. The reaction medium is stirredfor 3 days at a temperature of 95° C., hydrolyzed and extracted withethyl acetate. The organic phase is washed, dried (Na₂SO₄), filtered andconcentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(1-acetylazetidin-3-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (136 mg; 51%) is obtained in the form of apale yellow solid.

¹H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H), 1.42(hept, J=6.8 Hz, 1H), 1.73 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 3.07-3.20(m, 1H), 3.30-3.36 (m, 2H), 3.69 (dd, J=9.6, 5.6 Hz, 1H), 3.89 (t, J=9.0Hz, 1H), 3.98 (dd, J=8.5, 5.5 Hz, 1H), 4.18 (t, J=8.4 Hz, 1H), 4.71 (d,J=7.3 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.48 (dd,J=9.0, 1.7 Hz, 1H), 7.89-7.97 (m, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.31 (d,J=0.9 Hz, 1H)

MS: [M+H]=469

Example 10: Synthesis of 1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonicacid (4-ethylphenyl)isobutylamide

By following the same procedure as that for example 9,1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (22 mg; 36%) is obtained in the form of awhite solid.

¹H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.41(non, J=6.5 Hz, 1H), 1.85-1.97 (m, 2H), 2.15 (qd, J=12.3, 4.6 Hz, 2H),2.60 (q, J=7.6 Hz, 2H), 3.30-3.32 (m, 2H), 3.58 (td, J=11.9, 2.0 Hz,2H), 3.98-4.07 (m, 2H), 4.99 (td, J=11.3, 5.7 Hz, 1H), 6.98 (d, J=8.4Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.44 (dd, J=8.9, 1.7 Hz, 1H), 7.94 (d,J=8.9 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 8.32 (s, 1H)

MS: [M+H]=442

Example 11: Synthesis of1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide

A mixture of N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide(0.20 g; 0.56 mmol), cesium carbonate (0.27 g; 0.84 mmol) and1-(3-bromopyrrolidin-1-yl)ethanone (0.13 g; 0.67 mmol) in1-methyl-2-pyrrolidone (3 ml) is stirred for 5 hours at a temperature of80° C., hydrolyzed and extracted with ethyl acetate. The organic phaseis washed with water, dried (Na₂SO₄), filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (29 mg; 11%) is obtained in the form of awhite solid.

Mixture of two conformers: ¹H NMR (DMSO-d6) δ: 0.85 (dd, J=6.7, 1.1 Hz,6H), 1.18 (t, J=7.6 Hz, 3H), 1.33-1.50 (m, 1H), 2.01 (s, 3H), 2.60 (q,J=7.6 Hz, 2H), 3.34 (d, J=2.4 Hz, 2H), 3.46-3.54 (m, 1H), 3.59-3.65 (m,1H), 3.65-3.72 (m, 1H), 3.76-3.82 (m, 1H), 3.85 (dd, J=12.3, 6.8 Hz,1H), 4.05 (dd, J=10.8, 7.0 Hz, 1H), 5.57 (ddt, J=27.8, 11.5, 6.2 Hz,1H), 6.90-7.03 (m, 2H), 7.16-7.21 (m, 2H), 7.49 (ddd, J=8.8, 5.4, 1.7Hz, 1H), 7.92 (t, J=9.0 Hz, 1H), 8.11 (dd, J=3.4, 1.6 Hz, 1H), 8.32-8.41(m, 1H)

MS: [M+H]=469

With a procedure similar to that for intermediate 1.1, corresponding toa reductive amination between 1 equivalent of aldehyde and 1.15equivalents of aniline in tetrahydrofuran in the presence of 1.45equivalents of sodium triacetoxyborohydride, the anilines of the tablebelow are obtained:

Intermediate 12.1

cyclopropylmethyl(4- ethylphenyl)amine (300 mg; 46%) obtained in theform of an orange oil with a compliant ¹H NMR. MS: [M + H] = 176Intermediate 13.1

cyclobutylmethyl(4- ethylphenyl)amine (400 mg; 56%) obtained in the formof an orange oil with a compliant ¹H NMR. MS: [M + H] = 190 Intermediate14.1

cyclopentylmethyl(4- ethylphenyl)amine (19.3 g; 56%) obtained in theform of an amber-colored oil with a compliant ¹H NMR. MS: [M + H] = 190Intermediate 15.1

cyclobutylmethyl(4- ethylphenyl)amine (700 mg; 97%) obtained in the formof an oil with a compliant ¹H NMR. MS: [M + H] = 176 Intermediate 16.1

(tetrahydrofuran-3-ylmethyl)(4- ethylphenyl)amine (600 mg; 78%) obtainedin the form of an orange oil with a compliant ¹H NMR. MS: [M + H] = 206Intermediate 17.1

sec-butyl(4-ethylphenyl)amine (600 mg; 90%) obtained in the form of anorange oil with a compliant ¹H NMR. MS: [M + H] = 178 Intermediate 18.1

(4-ethylphenyl)(3-methylbutyl)amine (250 mg; 32%) obtained in the formof an orange oil with a compliant ¹H NMR. MS: [M + H] = 192 Intermediate19.1

4-ethyl-N-isopropylaniline (300 mg; 49%) obtained in the form of anorange oil with a compliant ¹H NMR. MS: [M + H] = 165 Intermediate 20.1

(4-ethylphenyl)(1-ethylpropyl)amine (700 mg; 98%) obtained in the formof an oil with a compliant ¹H NMR. MS: [M + H] = 192 Intermediate 21.1

ethyl(4-ethylphenyl)amine commercial Intermediate 22.1

propyl(4-ethylphenyl)amine (450 mg; 73%) obtained in the form of an oilwith a compliant ¹H NMR. MS: [M + H] = 165 Intermediate 23.1

butyl(4-ethylphenyl)amine (650 mg; 98%) obtained in the form of an oilwith a compliant ¹H NMR. MS: [M + H] = 178 Intermediate 24.1

(2,2,2-trifluoroethyl)(4- ethylphenyl)amine commercial Intermediate 25.1

isobutyl(4-isopropylphenyl)amine (600 mg; 93%) obtained in the form ofan oil with a compliant ¹H NMR. MS: [M + H] = 193 Intermediate 26.1

(5-chloro-2- fluorophenyl)isobutylamine (350 mg; 56%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 202 Intermediate27.1

(5-fluoro-2- methylphenyl)isobutylamine (802 mg; 61%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 182 Intermediate28.1

(3-fluoro-2- methylphenyl)isobutylamine (408 mg; 31%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 182 Intermediate29.1

(5-chlorophenyl)isobutylamine (655 mg; 100%) obtained in the form of anoil with a compliant ¹H NMR. MS: [M + H] = 185 Intermediate 30.1

(2-chlorophenyl)isobutylamine (655 mg; 100%) obtained in the form of anoil with a compliant ¹H NMR. MS: [M + H] = 184 Intermediate 31.1

(4-fluorophenyl)isobutylamine (684 mg; 100%) obtained in the form of anoil with a compliant ¹H NMR. MS: [M + H] = 169 Intermediate 32.1

(4-methylphenyl)isobutylamine (876 mg; 63%) obtained in the form of acolorless oil with a compliant ¹H NMR. MS: [M + H] = 164 Intermediate33.1

isobutyl-o-tolylamine (972.8 mg; 70%) obtained in the form of an oilwith a compliant ¹H NMR. MS: [M + H] = 164 Intermediate 34.1

(2,5-dimethylphenyl)isobutylamine (700 mg; 97%) obtained in the form ofan oil with a compliant ¹H NMR. MS: [M + H] = 179 Intermediate 35.1

(4-butyl-2- methylphenyl)isobutylamine (520 mg; 85%) obtained in theform of a clear yellow oil with a compliant ¹H NMR. MS: [M + H] = 220Intermediate 36.1

(2,4-dimethylphenyl)isobutylamine (1.15 g; 83%) obtained in the form ofan oil with a compliant ¹H NMR. MS: [M + H] = 179 Intermediate 37.1

(3.5-dimethylphenyl)isobutylamine (600 mg; 82%) obtained in the form ofa colorless oil with a compliant ¹H NMR. MS: [M + H] = 179 Intermediate38.1

(3-methylphenyl)isobutylamine (600 mg; 79%) obtained in the form of acolorless oil with a compliant ¹H NMR. MS: [M + H] = 164 Intermediate39.1

(3-methoxyphenyl)isobutylamine (600 mg; 82%) obtained in the form of acolorless oil with a compliant ¹H NMR. MS: [M + H] = 181 Intermediate40.1

(4- trifluoromethoxyphenyl)isobutylamine (600 mg; 100%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 235 Intermediate41.1

isobutyl(5-isopropylpyridin-2- yl)amine (600 mg; 93%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 193 Intermediate42.1

(3-methoxypyridin-2-yl)isobutylamine (450 mg; 68%) obtained in the formof an oil with a compliant ¹H NMR. MS: [M + H] = 181 Intermediate 43.1

(3-chlorobenzyl)isobutylamine (500 mg; 68%) obtained in the form of anoil with a compliant ¹H NMR. MS: [M + H] = 198 Intermediate 44.1

(3-methoxypyridin-2-yl)isobutylamine (600 mg; 100%) obtained in the formof an oil with a compliant ¹H NMR. MS: [M + H] = 232 Intermediate 45.1

(2-fluoro-6- methylphenyl)isobutylamine (560 mg; 44%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 182 Intermediate46.1

(4-chloro-2- methylphenyl)isobutylamine (892 mg; 71%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 182 Intermediate47.1

isobutyl(4-methoxy-2- methylphenyl)amine (980 mg; 77%) obtained in theform of an oil with a compliant ¹H NMR. MS: [M + H] = 193

With a procedure similar to that for intermediate 1.2, by reacting 1equivalent of N-substituted anilines (derived from the above table orcorresponding commercial products) with 1.3 equivalents of1H-indazole-5-sulfonyl chloride in tetrahydrofuran (20 vol) in thepresence of 6 equivalents of pyridine, the intermediates of the tablebelow are obtained:

Intermediate 12.2

1H-indazole-5-sulfonic acid cyclopropylmethyl(4- ethylphenyl)amide (450mg; 81%) is obtained in the form of colorless oil with a compliant ¹HNMR. MS: [M + H] = 356 Intermediate 13.2

1H-indazole-5-sulfonic acid cyclobutylmethyl(4- ethylphenyl)amide (590mg; 55%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 370 Intermediate 14.2

1H-indazole-5-sulfonic acid cyclopentyl(4-ethylphenyl)amide (250 mg;47%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 370 Intermediate 15.2

1H-indazole-5-sulfonic acid cyclobutyl(4-ethylphenyl)amide (80 mg; 51%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 356 Intermediate 16.2

1H-indazole-5-sulfonic acid (4- ethylphenyl)(tetrahydrofuran-3-ylmethyl)amide (800 mg; 78%) obtained in the form of a colorless oilwith a compliant ¹H NMR. MS: [M + H] = 386 Intermediate 17.2

1H-indazole-5-sulfonic acid sec- butyl(4-ethylphenyl)amide (310 mg; 56%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 358 Intermediate 18.2

1H-indazole-5-sulfonic acid (4- ethylphenyl)(3-methylbutyl)amide (220mg; 50%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 372 Intermediate 19.2

1H-indazole-5-sulfonic acid (4- ethylphenyl)isopropylamide (400 mg; 70%)obtained in the form of a colorless oil with a compliant ¹H NMR MS: [M +H] = 344 Intermediate 20.2

1H-indazole-5-sulfonic acid (4- ethylphenyl)(1-ethylpropyl)amide (40 mg;25%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 372 Intermediate 21.2

1H-indazole-5-sulfonic acid ethyl(4- ethylphenyl)amide (160 mg; 55%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 330 Intermediate 22.2

1H-indazole-5-sulfonic acid (4- ethylphenyl)propylamide (400 mg; 46%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 344 Intermediate 23.2

1H-indazole-5-sulfonic acid (4- ethylphenyl)butylamide (800 mg; 67%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 358 Intermediate 25.2

1H-indazole-5-sulfonic acid isobutyl(4-isopropylphenyl)amide (800 mg;76%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 372 Intermediate 26.2

1H-indazole-5-sulfonic acid (5- chloro-2-fluorophenyl)isobutylamide (120mg; 20%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 381 Intermediate 27.2

1H-indazole-5-sulfonic acid (5- fluoro-2-methylphenyl)isobutylamide (267mg; 53%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 362 Intermediate 28.2

1H-indazole-5-sulfonic acid (3- fluoro-2-methylphenyl)isobutylamide (137mg; 38%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 362 Intermediate 29.2

1H-indazole-5-sulfonic acid (5-chlorophenyl)isobutylamide (90 mg; 56%)obtained in the form of a white solid with a compliant ¹H NMR. MS: [M +H] = 364 Intermediate 31.2

1H-indazole-5-sulfonic acid (4- fluorophenyl)isobutylamide (100 mg; 66%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 348 Intermediate 32.2

1H-indazole-5-sulfonic acid isobutyl- p-tolylamide (770 mg; 81%)obtained in the form of a colorless oil with a compliant ¹H NMR MS: [M +H] = 344 Intermediate 33.2

1H-indazole-5-sulfonic acid isobutyl- o-tolylamide (481 mg; 46%)obtained in the form of a white solid with compliant ¹H NMR. MS: [M + H]= 344 Intermediate 34.2

1H-indazole-5-sulfonic acid (2,5- dimethylphenyl)isobutylamide (540 mg;59%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 358 Intermediate 35.2

1H-indazole-5-sulfonic acid (4-butyl- 2-methylphenyl)isobutylamide (650mg; 75%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 400 Intermediate 36.2

1H-indazole-5-sulfonic acid (2,4- dimethylphenyl)isobutylamide (500 mg;55%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 381 Intermediate 37.2

1H-indazole-5-sulfonic acid (3,5- dimethylphenyl)isobutylamide (140 mg;13%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 358 Intermediate 38.2

1H-indazole-5-sulfonic acid (3- methylphenyl)isobutylamide (310 mg; 27%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 344 Intermediate 39.2

1H-indazole-5-sulfonic acid (3- methoxyphenyl)isobutylamide (450 mg;62%) obtained in the form of a colorless oil with a compliant ¹H NMR.MS: [M + H] = 360 Intermediate 40.2

1H-indazole-5-sulfonic acid (4- trifluoromethoxyphenyl)isobutylamide(100 mg; 55%) obtained in the form of a colorless oil with a compliant¹H NMR. MS: [M + H] = 414 Intermediate 42.2

1H-indazole-5-sulfonic acid (3- methoxypyridin-2-yl)isobutylamide (300mg; 37%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 361 Intermediate 43.2

1H-indazole-5-sulfonic acid (3- chlorobenzyl)isobutylamide (50 mg; 30%)obtained in the form of a colorless oil with a compliant ¹H NMR. MS:[M + H] = 378 Intermediate 44.2

1H-indazole-5-sulfonic acid isobutyl(2- trifluoromethylbenzyl)amide (70mg; 39%) obtained in the form of a colorless oil with a compliant ¹HNMR. MS: [M + H] = 412 Intermediate 45.2

1H-indazole-5-sulfonic acid (2- fluoro-6-methylphenyl)isobutylamide (305mg; 65%) obtained in the form of a white solid with a compliant ¹H NMR.MS: [M + H] = 362 Intermediate 46.2

1H-indazole-5-sulfonic acid (4- fluoro-2-methylphenyl)isobutylamide (307mg; 65%) is obtained in the form of a yellowish solid with a compliant¹H NMR. MS: [M − H] = 360 Intermediate 47.2

1H-indazole-5-sulfonic acid isobutyl(4-methoxy-2- methylphenyl)amide(437 mg; 89%) obtained in the form of a colorless oil with a compliant¹H NMR. MS: [M + H] = 374 Intermediate 48.1

methyl 4-(1H-indazole-5- sulfonylamino)-3-methylbenzoate Obtained fromthe commercial amine. (480 mg; 63%) obtained in the form of a whitesolid with a compliant ¹H NMR. MS: [M − H] = 346 Intermediate 49.1

1H-indazole-5-sulfonic acid (4- cyano-2-methylphenyl)amide Obtained fromthe commercial amine. (330 mg; 80%) obtained in the form of abeige-colored solid with a compliant ¹H NMR. MS: [M − H] = 313

1. Synthesis of Intermediate 24.2

1H-indazole-5-sulfonic acid (4-ethylphenyl)(2,2,2-trifluoroethyl)amide

A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol),pyridine (3 ml), potassium iodide (7.3 mg; 0.04 mmol),4-dimethylaminopyridine (5.4 mg; 0.04 mmol) andN-(4-ethylphenyl)-N-(2,2,2-trifluoroethyl)amine hydrochloride (231 mg;0.96 mmol) is stirred for 16 hours at a temperature of 100° C.

Silver(I) fluoride (5.6 mg; 0.04 mmol) is added to the reaction medium,which is stirred for 3 days at a temperature of 80° C.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The 1H-indazole-5-sulfonicacid (4-ethylphenyl)(2,2,2-trifluoroethyl)amide (20 mg; 6%) is obtainedin the form of a clear yellow oil.

MS: [M+H]=384

2. Synthesis of Intermediate 30.2

1H-indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide

A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol),pyridine (3.0 ml), potassium iodide (14 mg; 0.08 mmol),4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and(2-chlorophenyl)isobutylamine (600 mg; 3.27 mmol) is stirred for 3 daysat a temperature of 100° C.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The 1H-indazole-5-sulfonicacid (2-chlorophenyl)isobutylamide (10 mg; 3%) is obtained in the formof a yellow oil with a compliant ¹H NMR.

MS: [M+H]=364

3. Synthesis of Intermediate 41.2

1H-indazole-5-sulfonic acid cyclopropylmethyl(4-ethylphenyl)amide

With the same procedure as that used for intermediate 30.2,1H-indazole-5-sulfonic acid cyclopropylmethyl(4-ethylphenyl)amide (40mg; 12%) is obtained in the form of a yellow oil with a compliant ¹HNMR.

MS: [M+H]=373

4. Synthesis of Intermediate 45.2

1H-indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide

(2-Fluoro-6-methylphenyl)isobutylamine (520 mg; 2.87 mmol) is added to asolution of 1H-indazole-5-sulfonyl chloride (297.4 mg; 1.30 mmol) inacetonitrile (1.25 ml) and the reaction medium is stirred for 40 minuteswith microwave irradiation at a temperature of 100° C. The reactionmedium is treated with 1N hydrochloric acid solution and extracted withethyl acetate. The organic phases are combined, washed with water, dried(MgSO₄), filtered and concentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The1H-indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide (305mg; 65%) is obtained in the form of a white solid with a compliant ¹HNMR.

MS: [M+H]=362

With a procedure similar to that described for the synthesis of example1, the addition of 1.2 equivalents of 4-(bromomethyl)tetrahydropyran to1 equivalent of N-substituted 1H-indazole-5-sulfonamide (preparedpreviously) in N,N-dimethylformamide in the presence of 1 equivalent ofcesium carbonate under microwave irradiation at 100° C. leads to thecompounds in the table below:

Example 12

N-(cyclopropylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide ¹H NMR (DMSO-d6) δ: 0.23-0.35 (m,2H), 0.64-0.77 (m, 1H), 1.12 (t, J = 7.6 Hz, 3H), 1.19-1.37 (m, 4H),2.10 (dtd, J = 11.1, 6.9, 3.4 Hz, 1H), 2.54 (q, J = 7.6 Hz, 2H), 3.17(td, J = 11.3, 3.0 Hz, 2H), 3.38 (d, J = 7.0 Hz, 2H), 3.76 (ddd, J =11.5, 4.4, 2.2 Hz, 2H), 4.32 (d, J = 7.1 Hz, 2H), 6.89-6.97 (m, 2H),7.11 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.9, 1.7 Hz, 1H), 7.85 (dt, J =8.8, 0.9 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.23 (d, J = 0.9 Hz, 1H).MS: [M + H] = 454 Example 13

N-(cyclobutylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide ¹H NMR (DMSO-d6) δ: 1.17 (t, J =7.6 Hz, 3H), 1.24-1.45 (m, 4H), 1.54-1.66 (m, 2H), 1.69-1.89 (m, 4H),2.10-2.30 (m, 2H), 2.59 (q, J = 7.6 Hz, 2H), 3.27 (td, J = 11.6, 2.4 Hz,2H), 3.56 (d, J = 7.5 Hz, 2H), 3.83 (ddd, 2H), 4.40 (d, J = 7.1 Hz, 2H),6.88-6.96 (m, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.31 (dd, J = 9.1, 1.8 Hz,1H), 7.75 (d, J = 9.1 Hz, 1H), 8.12-8.14 (m, 1H), 8.63 (d, J = 0.9 Hz,1H) MS: [M + H] = 468 Example 14

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acidcyclopentyl(4- ethylphenyl)amide ¹H NMR (DMSO-d6) δ: 1.12-1.26 (m, 5H),1.26-1.49 (m, 9H), 1.74 (dd, J = 12.2, 6.9 Hz, 2H), 2.61 (q, J = 7.6 Hz,2H), 3.24 (td, J = 11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.2 Hz,2H), 4.39 (d, J = 7.0 Hz, 2H), 4.46-4.57 (m, 1H), 6.87- 6.92 (m, 2H),7.17-7.23 (m, 2H), 7.69 (dd, J = 9.0, 1.8 Hz, 1H), 7.91-7.96 (m, 1H),8.21 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 468Example 15

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acidcyclobutyl(4- ethylphenyl)amide ¹H NMR (DMSO-d6) δ: 1.18 (t, J = 7.6 Hz,3H), 1.23-1.62 (m, 6H), 1.76 (dq, J = 12.0, 9.7 Hz, 2H), 2.05 (dddd, J =9.4, 7.4, 5.1, 2.5 Hz, 2H), 2.10-2.26 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H),3.24 (td, J = 11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.1 Hz, 2H),4.38 (dd, J = 8.5, 6.5 Hz, 3H), 6.80 (d, J = 8.3 Hz, 2H), 7.17 (d, J =8.3 Hz, 2H), 7.48 (dd, J = 9.0, 1.8 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H),8.11 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H) MS: [M + H] = 454 Example 16

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide ¹H NMR (DMSO-d6) δ: 1.18(t, J = 7.6 Hz, 3H), 1.25-1.43 (m, 4H), 1.58 (dq, J = 13.2, 6.8 Hz, 1H),1.76-1.90 (m, 1H), 2.06 (p, J = 5.9 Hz, 1H), 2.11-2.22 (m, 1H), 2.61 (q,J = 7.6 Hz, 2H), 3.24 (td, J = 11.3, 3.0 Hz, 2H), 3.42 (dd, J = 8.6, 5.2Hz, 1H), 3.48-3.62 (m, 4H), 3.71 (td, J = 8.1, 5.4 Hz, 1H), 3.76-3.89(m, 2H), 4.39 (d, J = 7.0 Hz, 2H), 6.91-7.00 (m, 2H), 7.14 -7.24 (m,2H), 7.48 (dd, J = 9.0, 1.7 Hz, 1H), 7.87-7.95 (m, 1H), 8.12 (d, J = 1.6Hz, 1H), 8.30 (d, J = 1.0 Hz, 1H) MS: [M + H] = 484 Example 17

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid sec-butyl(4-ethylphenyl)amide ¹H NMR (DMSO-d6) δ: 0.85 (t, J = 7.3 Hz, 3H), 0.93 (d,J = 6.7 Hz, 3H), 1.12- 1.25 (m, 5H), 1.26-1.44 (m, 4H), 2.62 (q, J = 7.6Hz, 2H), 3.24 (td, J = 11.3, 3.2 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.3Hz, 2H), 4.19 (dt, J = 7.8, 6.4 Hz, 1H), 4.39 (d, J = 7.1 Hz, 2H), 6.91(d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.68 (dd, J = 8.9, 1.8Hz, 1H), 7.94 (dt, J = 9.0, 0.9 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.30(d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 18

N-(4-ethylphenyl)-N-isopentyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide ¹H NMR (DMSO-d6) δ: 0.80 (d, J = 6.6 Hz, 6H),1.17 (t, J = 7.6 Hz, 5H), 1.25- 1.42 (m, 4H), 1.61 (hept, J = 6.7 Hz,1H), 2.09-2.24 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.23 (td, J = 11.2,3.1 Hz, 2H), 3.55 (t, J = 7.1 Hz, 2H), 3.81 (dt, J = 11.5, 3.3 Hz, 2H),4.38 (d, J = 7.1 Hz, 2H), 6.90- 6.99 (m, 2H), 7.12-7.22 (m, 2H), 7.47(dd, J = 9.0, 1.7 Hz, 1H), 7.87-7.96 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H),8.30 (d, J = 1.1 Hz, 1H) MS: [M + H] = 470 Example 19

N-(4-ethylphenyl)-N-isopropyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide ¹H NMR (DMSO-d6) δ: 0.95 (d, J = 6.7 Hz, 6H),1.19 (t, J = 7.6 Hz, 3H), 1.26- 1.45 (m, 4H), 2.63 (q, J = 7.6 Hz, 2H),3.24 (td, J = 11.3, 3.0 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.2 Hz, 2H),4.39 (d, J = 7.1 Hz, 2H), 4.47 (p, J = 6.7 Hz, 1H), 6.90- 6.98 (m, 2H),7.22 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 8.9, 1.8 Hz, 1H), 7.90-7.99 (m,1H), 8.22 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H). MS: [M + H] =442 Example 20

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(1-ethylpropyl)amide ¹H NMR (DMSO-d6) δ: 0.85 (t, J = 7.3Hz, 6H), 1.07-1.22 (m, 5H), 1.30 (ddd, J = 20.0, 9.0, 5.7 Hz, 6H), 2.16(s, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.23 (td, J = 11.2, 3.4 Hz, 2H), 3.81(d, J = 11.1 Hz, 2H), 3.91 (q, J = 6.5 Hz, 1H), 4.39 (d, J = 7.2 Hz,2H), 6.86-6.93 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 9.0 Hz,1H), 8.15 (d, J = 1.5 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H). MS: [M + H] =470 Example 22

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)propylamide ¹H NMR (DMSO-d6) δ: 0.83 (t, J = 7.3 Hz, 3H),1.17 (t, J = 7.6 Hz, 3H), 1.25- 1.44 (m, 6H), 2.24 (ddt, J = 10.9, 7.5,3.8 Hz, 1H), 2.60 (q, J = 7.5 Hz, 2H), 3.26 (td, J = 11.6, 2.5 Hz, 2H),3.50 (t, J = 6.9 Hz, 2H), 3.83 (ddd, J = 11.5, 4.5, 2.0 Hz, 2H), 4.40(d, J = 7.1 Hz, 2H), 6.93-7.02 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.29(dd, J = 9.1, 1.8 Hz, 1H), 7.70-7.80 (m, 1H), 8.12 (dd, J = 1.9, 0.8 Hz,1H), 8.62 (d, J = 11.0 Hz, 1H) MS: [M + H] = 442 Example 23

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-ethylphenyl)amide ¹H NMR (DMSO-d6) δ: 0.74-0.88 (m, 3H), 1.17 (t, J =7.6 Hz, 3H), 1.23-1.45 (m, 8H), 2.24 (ddt, J = 11.0, 7.6, 3.8 Hz, 1H),2.60 (q, J = 7.6 Hz, 2H), 3.26 (td, J = 11.5, 2.5 Hz, 2H), 3.54 (q, J =4.4 Hz, 2H), 3.83 (ddd, J = 11.5, 4.3, 2.0 Hz, 2H), 4.40 (d, J = 7.2 Hz,2H), 6.93-7.01 (m, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 9.1, 1.8Hz, 1H), 7.74 (dd, J = 9.0, 1.0 Hz, 1H), 8.11-8.14 (m, 1H), 8.62 (d, J =0.9 Hz, 1H). MS: [M + H] = 456 Example 25

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-isopropylphenyl)amide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 6H), 1.19(d, J = 6.9 Hz, 6H), 1.25- 1.50 (m, 5H), 2.11-2.22 (m, 1H), 2.88 (hept,J = 6.8 Hz, 1H), 3.23 (td, J = 11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.6,4.4, 2.2 Hz, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.94- 7.03 (m, 2H), 7.20 (d,J = 8.4 Hz, 2H), 7.44 (dd, J = 8.9, 1.8 Hz, 1H), 7.85-7.94 (m, 1H), 8.09(d, J = 1.7 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H) MS: [M + H] = 470 Example26

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-chloro-2-fluorophenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 6H),1.21-1.49 (m, 5H), 2.17 (dd, J = 10.5, 5.9 Hz, 1H), 3.23 (td, J = 11.1,3.3 Hz, 2H), 3.76-3.87 (m, 2H), 4.40 (d, J = 7.0 Hz, 2H), 7.15 (dd, J =6.5, 2.7 Hz, 1H), 7.35 (dd, J = 10.1, 8.9 Hz, 1H), 7.50 (ddd, J = 8.8,4.1, 2.6 Hz, 1H), 7.56 (dd, J = 9.0, 1.8 Hz, 1H), 7.92-7.99 (m, 1H),8.20 (d, J = 1.7 Hz, 1H), 8.33 (d, J = 1.0 Hz, 1H). MS: [M + H] = 480Example 27

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-fluoro-2-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H),0.95 (d, J = 6.6 Hz, 3H), 1.22- 1.49 (m, 5H), 2.07-2.25 (m, 1H), 2.27(s, 3H), 3.13 (dd, J = 13.2, 4.7 Hz, 1H), 3.23 (td, J = 11.2, 3.4 Hz,2H), 3.43 (dd, J = 13.2, 9.1 Hz, 1H), 3.81 (dt, J = 11.5, 3.2 Hz, 2H),4.40 (d, J = 7.1 Hz, 2H), 6.45 (dd, J = 10.1, 2.7 Hz, 1H), 7.12 (td, J =8.3, 2.7 Hz, 1H), 7.35 (dd, J = 8.6, 6.6 Hz, 1H), 7.51 (dd, J = 8.9, 1.8Hz, 1H), 7.91- 7.99 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 0.9Hz, 1H). MS: [M + H] = 460 Example 28

1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid (3-fluoro-2-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H),0.94 (d, J = 6.5 Hz, 3H), 1.18- 1.52 (m, 5H), 2.08-2.27 (m, 4H), 3.13(dd, J = 13.1, 4.8 Hz, 1H), 3.23 (td, J = 11.2, 3.1 Hz, 2H), 3.46 (dd, J= 13.2, 9.0 Hz, 1H), 3.73-3.88 (m, 2H), 4.39 (d, J = 7.1 Hz, 2H), 6.52(d, J = 8.1 Hz, 1H), 7.06- 7.26 (m, 2H), 7.52 (dd, J = 8.9, 1.8 Hz, 1H),7.93 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 1.0 Hz,1H). MS: [M + H] = 460 Example 29

1-tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-chlorophenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H),1.21-1.50 (m, 5H), 3.23 (td, J = 11.2, 3.2 Hz, 2H), 3.38 (d, J = 7.3 Hz,2H), 3.80 (s, 2H), 4.38 (d, J = 7.1 Hz, 2H), 7.08 (dt, J = 7.0, 2.0 Hz,1H), 7.13 (t, J = 1.9 Hz, 1H), 7.34-7.40 (m, 2H), 7.41- 7.44 (m, 1H),7.91 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 1.0 Hz,1H). MS: [M + H] = 462 Example 30

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide ¹H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.2Hz, 6H), 1.37 (td, J = 10.9, 9.9, 4.0 Hz, 4H), 1.55 (dt, J = 13.5, 6.8Hz, 2H), 2.22 (s, 1H), 3.28 (td, J = 11.1, 4.0 Hz, 2H), 3.36 (dd, J =7.2, 1.8 Hz, 2H), 3.89 (dt, J = 11.6, 3.3 Hz, 2H), 4.22 (d, J = 7.1 Hz,2H), 7.19 (m, 3H), 7.25-7.30 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.61(dd, J = 8.9, 1.7 Hz, 1H), 8.03 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H). MS:[M + H] = 462 Example 31

1-(tetrahydrouyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-fluorophenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H),1.23-1.48 (m, 5H), 2.16 (ddd, J = 11.0, 6.9, 4.2 Hz, 1H), 3.23 (td, J =11.3, 2.9 Hz, 2H), 3.35 (s, 2H), 3.82 (ddd, J = 11.5, 4.5, 2.2 Hz, 2H),4.38 (d, J = 7.0 Hz, 2H), 7.05-7.22 (m, 4H), 7.45 (dd, J = 8.9, 1.7 Hz,1H), 7.90 (d, J = 8.9 Hz, 1H), 8.07 (d, J = 1.7 Hz, 1H), 8.30 (s, 1H).MS: [M + H] = 446 Example 32

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-p-tolylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.7 Hz, 6H), 1.23-1.48 (m,5H), 2.05-2.25 (m, 1H), 2.29 (s, 3H), 3.24 (td, J = 11.3, 2.8 Hz, 3H),3.32 (td, 2H), 3.82 (dd, J = 11.3, 3.7 Hz, 2H), 4.38 (d, J = 7.1 Hz,2H), 6.89-6.95 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 8.9, 1.8Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.30 (s,1H). MS: [M + H] = 442 Example 33

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-o-tolylamide ¹H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz, 3H), 0.96 (d, J =6.6 Hz, 3H), 1.24- 1.50 (m, 5H), 2.07-2.26 (m, 1H), 2.30 (s, 3H), 3.13(dd, J = 13.2, 4.9 Hz, 1H), 3.24 (td, J = 11.0, 2.9 Hz, 2H), 3.45 (dd, J= 13.1, 8.9 Hz, 1H), 3.82 (dd, J = 13.4, 2.4 Hz, 2H), 4.40 (d, J = 7.1Hz, 2H), 6.62 (dd, J = 8.1, 1.3 Hz, 1H), 7.08 (td, J = 7.7, 1.7 Hz, 1H),7.24 (td, J = 7.5, 1.3 Hz, 1H), 7.31 (dd, J = 7.8, 1.6 Hz, 1H), 7.53(dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 8.13 (s, 1H), 8.32(s, 1H). MS: [M + H] = 442 Example 34

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5-dimethylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz,3H), 0.96 (d, J = 6.6 Hz, 3H), 1.26- 1.38 (m, 4H), 1.44 (dtd, J = 8.9,6.7, 4.8 Hz, 1H), 2.03 (s, 3H), 2.12-2.22 (m, 1H), 2.23 (s, 3H), 3.07(dd, J = 13.1, 4.8 Hz, 1H), 3.19-3.27 (m, 2H), 3.43 (dd, J = 13.1, 8.9Hz, 1H), 3.81 (dq, J = 10.8, 3.4 Hz, 2H), 4.41 (d, J = 7.0 Hz, 2H), 6.29(d, J = 1.7 Hz, 1H), 7.04 (dd, J = 7.8, 1.8 Hz, 1H), 7.17 (d, J = 7.7Hz, 1H), 7.49 (dd, J = 9.0, 1.7 Hz, 1H), 7.93 (dt, J = 9.0, 0.9 Hz, 1H),8.13 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456Example 35

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-butyl-2-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.75 (d, J = 6.6 Hz, 3H),0.90 (t, J = 7.3 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.24-1.47 (m, 8H),1.48- 1.59 (m, 2H), 2.16 (s, 1H), 2.25 (s, 3H), 3.09 (dd, J = 13.1, 4.9Hz, 1H), 3.24 (td, J = 11.1, 3.2 Hz, 2H), 3.37-3.46 (m, 1H), 3.77-3.88(m, 2H), 4.39 (d, J = 7.0 Hz, 2H), 6.52 (d, J = 8.2 Hz, 1H), 6.88 (dd, J= 8.2, 2.2 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 9.0, 1.7 Hz,1H), 7.85- 7.98 (m, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz,1H) MS: [M + H] = 498 Example 36

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4-dimethylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz,3H), 0.96 (d, J = 6.5 Hz, 3H), 1.22- 1.48 (m, 5H), 2.09 (d, J = 4.8 Hz,1H), 2.11-2.21 (m, 1H), 2.25 (d, J = 4.1 Hz, 6H), 3.08 (dd, J = 13.1,4.8 Hz, 1H), 3.24 (td, J = 11.2, 3.2 Hz, 2H), 3.43 (dd, J = 13.1, 8.9Hz, 1H), 3.76-3.87 (m, 2H), 4.40 (d, J = 7.0 Hz, 2H), 6.48 (d, J = 8.1Hz, 1H), 6.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.53(dd, J = 9.0, 1.7 Hz, 1H), 7.90-7.96 (m, 1H), 8.13 (d, J = 1.7 Hz, 1H),8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 37

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3,5-dimethylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz,6H), 1.22-1.38 (m, 4H), 1.44 (hept, J = 6.8 Hz, 1H), 2.16 (s, 7H), 3.23(td, J = 11.1, 3.6 Hz, 2H), 3.29 (d, J = 7.3 Hz, 2H), 3.76-3.85 (m, 2H),4.39 (d, J = 7.0 Hz, 2H), 6.58-6.63 (m, 2H), 6.94 (s, 1H), 7.42 (dd, J =8.8, 1.7 Hz, 1H), 7.87- 7.92 (m, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.31 (d,J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 38

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J = 6.6 Hz, 6H),1.23-1.52 (m, 5H), 2.22 (s, 4H), 3.23 (td, J = 11.3, 3.2 Hz, 2H), 3.77-3.87 (m, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.78-6.89 (m, 2H), 7.10-7.15 (m,1H), 7.20 (t, J = 7.7 Hz, 1H), 7.85-7.93 (m, 1H), 8.08 (d, J = 1.6 Hz,1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 442 Example 39

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-methoxyphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.86 (d, J = 6.6 Hz,6H), 1.21-1.38 (m, 4H), 1.45 (hept, J = 6.8 Hz, 1H), 3.23 (td, J = 11.3,3.2 Hz, 2H), 3.61 (s, 3H), 3.81 (dt, J = 11.7, 2.7 Hz, 2H), 4.38 (d, J =7.0 Hz, 2H), 6.53 (t, J = 2.3 Hz, 1H), 6.66 (ddd, J = 7.9, 2.0, 0.9 Hz,1H), 6.89 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H),7.46 (dd, J = 8.9, 1.7 Hz, 1H), 7.88-7.94 (m, 1H), 8.10 (d, J = 1.6 Hz,1H), 8.30 (d, J = 0.8 Hz, 1H) MS: [M + H] = 458 Example 40

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-trifluoromethoxyphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.85 (d, J =6.6 Hz, 6H), 1.24-1.47 (m, 5H), 2.10-2.20 (m, 1H), 3.23 (td, J = 11.3,2.9 Hz, 2H), 3.37 (d, J = 7.4 Hz, 2H), 3.80 (s, 2H), 4.38 (d, J = 7.1Hz, 2H), 7.20-7.26 (m, 2H), 7.32-7.37 (m, 2H), 7.43 (dd, J = 9.0, 1.8Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 8.30 (d, J= 0.9 Hz, 1H); MS: [M + H] = 512 Example 41

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(5-isopropylpyridin-2-yl)amide ¹H NMR (Chloroform-d) δ: 0.82 (d, J = 6.7Hz, 6H), 1.20 (s, 6H), 1.30-1.44 (m, 4H), 2.15-2.28 (m, 1H), 2.87 (p, J= 7.0 Hz, 1H), 3.28 (td, J = 11.5, 3.0 Hz, 2H), 3.42 (d, J = 7.3 Hz,2H), 3.86-3.93 (m, 2H), 4.18 (d, J = 7.2 Hz, 2H), 7.29-7.33 (m, 1H),7.40 (dd, J = 9.0, 1.7 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.55 (dd, J =8.3, 2.5 Hz, 1H), 8.01 (d, J = 0.8 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H),8.08 (d, J = 2.5 Hz, 1H). MS: [M + H] = 471 Example 42

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-methoxypyridin-2-yl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.86 (d, J = 6.6Hz, 6H), 1.20-1.37 (m, 4H), 1.57 (hept, J = 6.9 Hz, 1H), 2.03-2.24 (m,1H), 3.12- 3.26 (m, 3H), 3.42 (s, 3H), 3.53 (d, J = 7.1 Hz, 2H),3.71-3.87 (m, 2H), 4.37 (d, J = 7.1 Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H),7.12 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 9.0, 1.8 Hz, 1H), 7.73-7.82 (m,1H), 7.88 (dd, J = 9.0, 1.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.29 (d,J = 0.9 Hz, 1H) MS: [M + H] = 459 Example 43

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-chlorobenzyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.70 (d, J = 6.6 Hz, 6H),1.25-1.42 (m, 4H), 1.58 (dt, J = 13.6, 6.9 Hz, 1H), 2.92 (d, J = 7.6 Hz,2H), 3.24 (td, J = 11.3, 3.2 Hz, 2H), 3.82 (d, J = 11.2 Hz, 2H), 4.33(s, 2H), 4.40 (d, J = 7.1 Hz, 2H), 7.24-7.37 (m, 4H), 7.80 (dd, J = 9.0,1.7 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H), 8.37(d, J = 1.7 Hz, 1H) MS: [M + H] = 476 Example 44

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(2-trifluoromethylbenzyl)amide ¹H NMR (DMSO-d6) δ: 0.70 (d, J = 6.6 Hz,6H), 1.23-1.43 (m, 5H), 2.97 (d, J = 7.2 Hz, 2H), 3.24 (td, J = 11.3,3.0 Hz, 2H), 3.82 (d, J = 10.7 Hz, 2H), 4.40 (d, J = 7.1 Hz, 2H), 4.48(s, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.70 (q, J = 7.6 Hz, 2H), 7.78 (d, J= 7.9 Hz, 1H), 7.83 (dd, J = 8.9, 1.8 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H),8.39 (d, J = 1.7 Hz, 1H) MS: [M + H] = 510 Example 45

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H),0.93 (d, J = 6.6 Hz, 3H), 1.21- 1.39 (m, 4H), 1.41-1.57 (m, 1H), 2.08-2.25 (m, 1H), 2.28 (s, 3H), 3.15 (dd, J = 13.7, 5.8 Hz, 1H), 3.23 (td, J= 11.0, 3.7 Hz, 2H), 3.45 (dd, J = 13.6, 7.9 Hz, 1H), 3.81 (dt, J =11.4, 3.3 Hz, 2H), 4.39 (d, J = 7.0 Hz, 2H), 7.00 (ddd, J = 10.2, 8.3,1.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.23- 7.36 (m, 1H), 7.63 (dd, J =8.9, 1.8 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H),8.31 (d, J = 1.0 Hz, 1H) MS: [M + H] = 460 Example 46

1-(tetrahyropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-fluoro-2-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.77 (d, J = 6.7 Hz, 3H),0.95 (d, J = 6.5 Hz, 3H), 1.24- 1.50 (m, 5H), 2.11-2.24 (m, 1H), 2.29(s, 3H), 3.10 (dd, J = 13.1, 4.8 Hz, 1H), 3.23 (td, J = 11.2, 3.2 Hz,2H), 3.45 (dd, J = 13.2, 8.9 Hz, 1H), 3.82 (dt, J = 11.6, 2.7 Hz, 2H),4.39 (d, J = 7.1 Hz, 2H), 6.66 (dd, J = 8.9, 5.5 Hz, 1H), 6.92 (td, J =8.4, 3.1 Hz, 1H), 7.18 (dd, J = 9.8, 3.0 Hz, 1H), 7.53 (dd, J = 8.9, 1.7Hz, 1H), 7.93 (dd, J = 9.0, 0.9 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.32(d, J = 0.9 Hz, 1H) MS: [M + H] = 460 Example 47

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(4-methoxy-2-methylphenyl)amide 1H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7 Hz,3H), 0.96 (d, J = 6.6 Hz, 3H), 1.23- 1.53 (m, 5H), 2.08-2.21 (m, 1H),2.24 (s, 3H), 3.07 (dd, J = 13.0, 4.8 Hz, 1H), 3.24 (td, J = 11.2, 3.2Hz, 2H), 3.43 (dd, J = 13.1, 8.9 Hz, 1H), 3.73 (s, 3H), 3.82 (dt, J =11.4, 3.3 Hz, 2H), 4.39 (d, J = 7.1 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H),6.61 (dd, J = 8.8, 3.0 Hz, 1H), 6.85 (d, J = 2.9 Hz, 1H), 7.53 (dd, J =8.9, 1.7 Hz, 1H), 7.87- 7.96 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.31 (d,J = 0.9 Hz, 1H) MS: [M + H] = 472 Example 48

methyl 4-{isobutyl[1-(tetrahydropyran- 4-ylmethyl)-1H-indazole-5-sulfonyl]amino}-3-methylbenzoate ¹H NMR (DMSO-d6) δ: 0.76 (d, J = 6.7Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.23- 1.49 (m, 5H), 2.09-2.23 (m,1H), 2.37 (s, 3H), 3.15 (dd, J = 13.2, 4.8 Hz, 1H), 3.24 (td, J = 11.2,3.0 Hz, 2H), 3.46 (dd, J = 13.3, 8.9 Hz, 1H), 3.75-3.88 (m, 5H), 4.40(d, J = 7.1 Hz, 2H), 6.80 (d, J = 8.3 Hz, 1H), 7.51 (dd, J = 8.9, 1.7Hz, 1H), 7.65 (dd, J = 8.3, 2.2 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.93(d, J = 8.9 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H)MS: [M + H] = 500 Example 49

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-cyano-2-methylphenyl)isobutylamide ¹H NMR (DMSO-d6) δ: 0.76 (d, J = 6.6 Hz, 3H),0.93 (d, J = 6.5 Hz, 3H), 1.21- 1.48 (m, 5H), 2.06-2.25 (m, 1H), 2.35(s, 3H), 3.07-3.29 (m, 3H), 3.45 (dd, J = 13.3, 9.0 Hz, 1H), 3.82 (dd, J= 10.1, 3.2 Hz, 2H), 4.40 (d, J = 7.0 Hz, 2H), 6.88 (d, J = 8.3 Hz, 1H),7.52 (dd, J = 9.0, 1.8 Hz, 1H), 7.59 (dd, J = 8.2, 2.1 Hz, 1H), 7.86 (d,J = 2.0 Hz, 1H), 7.94 (dd, J = 9.0, 0.9 Hz, 1H), 8.15 (d, J = 1.6 Hz,1H), 8.33 (d, J = 1.0 Hz, 1H). MS: [M + H] = 467

Example 50: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)(tetrahydropyran-4-ylmethyl)amide

1. Synthesis of Intermediate 50.1

1H-indazole-5-sulfonic acid (4-ethylphenyl)amide

A mixture of 1H-indazole-5-sulfonyl chloride (1.00 g; 4.39 mmol),pyridine (5.0 ml) and 4-ethylaniline (603 μl; 4.82 mmol) is stirred for4 hours at 50° C. The reaction medium is diluted with ethyl acetate andextracted. The organic phase is washed with saturated ammonium chloridesolution, with saturated sodium hydrogen carbonate solution and withwater. It is dried (MgSO₄), filtered and concentrated to dryness.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.32 g; 100%) isobtained in the form of an orange oil with a compliant ¹H NMR.

MS: [M+H]=302

2. Synthesis of Compound 5 According to the Invention

A mixture of 1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.30 g;4.31 mmol), cesium carbonate (2.11 g; 6.47 mmol) and4-(bromomethyl)tetrahydropyran (680 μl; 5.18 mmol; 1.20 eq.) inN-methyl-2-pyrrolidone (10 ml) is stirred for 16 hours at a temperatureof 50° C. The reaction medium is diluted with ethyl acetate (30 ml). Theorganic phase is washed with saturated NH₄Cl solution (20 ml), withsaturated NaHCO₃ solution (20 ml) and with water (20 ml). The organicphase is dried (MgSO₄), filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)(tetrahydropyran-4-ylmethyl)amide (360 mg; 17%) isobtained in the form of a white solid.

¹H NMR (DMSO-d6) δ: 1.08-1.23 (m, 5H), 1.25-1.47 (m, 5H), 1.52-1.62 (m,2H), 2.60 (q, J=7.5 Hz, 2H), 3.13 (td, J=11.6, 2.2 Hz, 2H), 3.23 (td,J=11.3, 3.0 Hz, 2H), 3.43 (d, J=7.2 Hz, 2H), 3.72-3.87 (m, 4H), 4.38 (d,J=7.1 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.46 (dd,J=9.0, 1.7 Hz, 1H), 7.84-7.98 (m, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.29 (d,J=0.9 Hz, 1H)

MS: [M+H]=498

-   -   Another fraction is obtained corresponding to the mixture below:

Intermediate 51.1: Mixture ofN-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamideandN-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide.

The mixture ofN-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamideandN-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide(170.00 mg; 10%) is obtained in the form of a solid with a compliant ¹HNMR.

MS: [M+H]=400

Example 51: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acidcyclopropyl(4-ethylphenyl)amide

A spatulaful of molecular sieves is added to a mixture ofN-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamideandN-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulfonamide(170 mg; 0.43 mmol), triethylamine (180 μl; 1.28 mmol), copper(II)acetate (232 mg; 1.28 mmol) and cyclopropylboronic acid (220 mg; 2.55mmol) in dichloromethane (3 ml).

The reaction medium is stirred for 16 hours at room temperature under 1atmosphere of oxygen and filtered through Celite, which is rinsed withdichloromethane (50 ml) and with water (20 ml). The organic phase isextracted, washed with a mixture (1/1) of aqueous ammonia and saturatedNH₄Cl solution (2×50 ml) and then with water (50 ml), dried (MgSO₄),filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acidcyclopropyl(4-ethylphenyl)amide 002 (40 mg; 21%) is obtained in the formof a white solid.

¹H NMR (DMSO-d6) δ: 0.62 (t, J=3.2 Hz, 2H), 0.76 (dt, J=7.1, 3.6 Hz,2H), 1.14-1.22 (m, 4H), 1.23-1.42 (m, 4H), 2.16 (dd, J=10.8, 5.1 Hz,1H), 2.58-2.71 (m, 3H), 3.17-3.29 (m, 3H), 3.76-3.89 (m, 2H), 4.38 (d,J=7.1 Hz, 2H), 6.87-7.02 (m, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.46 (dd,J=8.8, 1.7 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.33(d, J=0.9 Hz, 1H)

MS: [M+H]=440

Example 52: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acidisobutyl(2-trifluoromethylphenyl)amide

1. Synthesis of Intermediate 52.1

1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide

A mixture of 1H-indazole-5-sulfonyl chloride (500.0 mg; 2.19 mmol),pyridine (3.0 ml) and 2-(trifluoromethyl)aniline (306.18 μl; 2.41 mmol)is stirred for 16 hours at a temperature of 40° C. The reaction mediumis diluted with ethyl acetate and extracted. The organic phase is washedwith saturated ammonium chloride solution, with saturated sodiumhydrogen carbonate solution and with water. It is dried (MgSO₄),filtered and concentrated to dryness.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 40% of ethyl acetate).

The 1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide (300 mg;40%) is obtained in the form of a white solid with a compliant ¹H NMR.

MS: [M+H]=342

2. Synthesis of Compound 58 According to the Invention

Cesium carbonate (30 mg; 1.32 mmol) and 4-(bromomethyl)tetrahydropyran(127 μl; 0.97 mmol) are added to a solution of 1H-indazole-5-sulfonicacid (2-trifluoromethylphenyl)amide (300 mg; 0.88 mmol) in1-methyl-2-pyrrolidone (3 ml). The reaction medium is stirred for 16hours at room temperature. 1-Bromo-2-methylpropane (287 μl; 2.64 mmol)is added and the reaction medium is stirred for 6 hours at 80° C. Thereaction medium is diluted with ethyl acetate, washed with saturatedammonium chloride solution and then with saturated sodium hydrogencarbonate solution and with water. The organic phase is dried (MgSO₄),filtered and concentrated to dryness.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acidisobutyl(2-trifluoromethylphenyl)amide (80 mg; 16%) is obtained in theform of a beige-colored solid.

¹H NMR (DMSO-d6) δ: 0.71 (d, J=6.7 Hz, 3H), 0.85-0.93 (m, 3H), 1.25-1.43(m, 4H), 1.48 (dtd, J=8.8, 6.6, 4.6 Hz, 1H), 2.12-2.25 (m, 1H), 3.15(dd, J=13.4, 4.6 Hz, 1H), 3.24 (td, J=10.8, 10.4, 2.2 Hz, 2H), 3.46 (dd,J=13.4, 8.8 Hz, 1H), 3.78-3.86 (m, 2H), 4.41 (d, J=7.1 Hz, 2H), 6.99(dd, J=5.7, 3.7 Hz, 1H), 7.56 (dd, J=9.0, 1.7 Hz, 1H), 7.58-7.64 (m,2H), 7.85 (dt, J=5.6, 3.7 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.18-8.24 (m,1H), 8.35 (s, 1H).

MS: [M+H]=496

Example 53: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acidisobutyl(4-trifluoromethylphenyl)amide

1. Synthesis of Intermediate 53.1

1H-indazole-5-sulfonic acid (4-trifluoromethylphenyl)amide

A mixture of 1H-indazole-5-sulfonyl chloride (250.0 mg; 1.10 mmol) and4-(trifluoromethyl)aniline (388.6 μl; 2.41 mmol) in acetonitrile (1.7ml) is stirred for 40 minutes at a temperature of 100° C. undermicrowave irradiation. The reaction medium is diluted with ethyl acetateand extracted.

The organic phase is washed with saturated ammonium chloride solution,with saturated sodium hydrogen carbonate solution and with water. It isdried (MgSO₄), filtered and concentrated to dryness.

The 1H-indazole-5-sulfonic acid (4-trifluoromethylphenyl)amide (297 mg;79%) is obtained in the form of a yellowish solid with a compliant ¹HNMR.

MS: [M+H]=342

2. Synthesis of Compound 59 According to the Invention

With a procedure similar to that described for example 52,1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acidisobutyl(4-trifluoromethylphenyl)amide (178 mg; 40%) is obtained in theform of a white solid.

¹H NMR (DMSO-d6) δ: 0.84 (d, J=6.6 Hz, 6H), 1.22-1.51 (m, 5H), 2.07-2.24(m, 1H), 3.23 (td, J=11.4, 2.9 Hz, 2H), 3.42 (d, J=7.3 Hz, 2H), 3.81(ddd, J=11.6, 4.2, 2.1 Hz, 2H), 4.37 (d, J=7.1 Hz, 2H), 7.37 (d, J=8.2Hz, 2H), 7.43 (dd, J=8.9, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.91 (d,1H), 8.13 (d, J=1.6 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H).

MS: [M+H]=496

Example 54: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(2-cyano-4-methylphenyl)isobutylamide

1. Synthesis of Intermediate 54.1

1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)amide

With a procedure similar to that described for intermediate 53.1,1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)amide (342.4 mg;100%) is obtained in the form of a yellowish solid with a compliant ¹HNMR.

MS: [M+H]=313

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonicacid (2-cyano-4-methylphenyl)isobutylamide (compound 70)

With a procedure similar to that described for example 52,1-(tetrahydropyran-4-ylmethyl)-2H-indazole-5-sulfonic acid(2-cyano-4-methylphenyl)isobutylamide (129.7 mg; 20%) is obtained in theform of a white solid.

¹H NMR (Chloroform-d) δ: 0.93 (d, J=6.7 Hz, 6H), 1.42-1.53 (m, 4H),1.54-1.67 (m, 1H), 2.21-2.39 (m, 1H), 2.42 (s, 3H), 3.37 (td, J=11.3,3.5 Hz, 2H), 3.45 (d, J=7.2 Hz, 2H), 3.98 (dt, J=11.7, 2.6 Hz, 2H), 4.32(d, J=7.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 1H), 7.41 (dd, J=8.2, 2.1 Hz, 1H),7.45 (d, J=2.1 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.78 (dd, J=8.9, 1.6 Hz,1H), 8.15 (d, J=1.0 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H).

MS: [M+H]=467

Example 55: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4,6-dimethylpyridin-3-yl)isobutylamide

1. Synthesis of Intermediate 55.1

1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)amide

With a procedure similar to that described for intermediate 53.1,1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)amide (151 mg;46%) is obtained in the form of a yellowish solid with a compliant ¹HNMR.

MS: [M+H]=303

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonicacid (4,6-dimethylpyridin-3-yl)isobutylamide

With a procedure similar to that described for example 52,1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4,6-dimethylpyridin-3-yl)isobutylamide (17 mg; 7%) is obtained in theform of a white solid.

¹H NMR (DMSO-d6) δ: 0.78 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H),1.18-1.56 (m, 5H), 2.13-2.27 (m, 4H), 2.41 (s, 3H), 3.19-3.29 (m, 3H),3.44 (dd, J=13.3, 8.6 Hz, 1H), 3.78-3.89 (m, 2H), 4.40 (d, J=7.0 Hz,2H), 7.21 (s, 1H), 7.56 (dd, J=8.9, 1.8 Hz, 1H), 7.68 (s, 1H), 7.96 (d,J=8.8 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 8.33 (s, 1H).

MS: [M+H]=457

Example 56: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-dimethylaminophenyl)isobutylamide

1. Synthesis of Intermediate 56.1

1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)amide

With a procedure similar to that described for intermediate 53.1,1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)amide (281 mg; 81%)is obtained in the form of a fluffy white solid with a compliant ¹H NMR.

MS: [M+H]=317

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonicacid (4-dimethylaminophenyl)isobutylamide (compound 72)

With a procedure similar to that described for example 52,1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-dimethylaminophenyl)isobutylamide (19 mg; 4%) is obtained in the formof a white solid.

¹H 1H NMR (Chloroform-d) δ: 0.94 (d, J=6.7 Hz, 6H), 1.38-1.55 (m, 3H),1.62 (dd, J=13.2, 6.3 Hz, 2H), 2.31 (dt, J=11.0, 5.6 Hz, 1H), 2.97 (s,6H), 3.30 (d, J=7.3 Hz, 2H), 3.38 (td, J=11.3, 3.1 Hz, 2H), 3.99 (ddd,J=11.7, 4.4, 2.1 Hz, 2H), 4.31 (d, J=7.1 Hz, 2H), 6.60 (d, J=8.4 Hz,2H), 6.84-6.91 (m, 2H), 7.41-7.46 (m, 1H), 7.60 (dd, J=8.9, 1.6 Hz, 1H),8.08 (d, J=1.7 Hz, 1H), 8.11 (d, J=0.9 Hz, 1H).

MS: [M+H]=471

Example 57: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(2-fluoro-4-methylphenyl)isobutylamide

1. Synthesis of Intermediate 57.1

1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)amide

With a procedure similar to that described for intermediate 53.1,1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)amide (189 mg; 94%)is obtained in the form of a yellowish solid with a compliant ¹H NMR.

MS: [M+H]=306

2. Synthesis of 1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonicacid (2-fluoro-4-methylphenyl)isobutylamide

With a procedure similar to that described for example 52,1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(2-fluoro-4-methylphenyl)isobutylamide (19 mg; 4%) is obtained in theform of a white solid.

¹H 1H NMR (Chloroform-d) δ: 0.93 (d, J=6.6 Hz, 6H), 1.47 (td, J=11.2,10.7, 4.2 Hz, 3H), 1.54-1.69 (m, 2H), 2.30 (dd, J=10.7, 4.6 Hz, 1H),2.36 (s, 3H), 3.24-3.47 (m, 5H), 3.95-4.03 (m, 2H), 4.31 (d, J=7.1 Hz,2H), 6.82 (dd, J=11.5, 1.8 Hz, 1H), 6.94 (dd, J=8.2, 1.8 Hz, 1H), 7.16(t, J=8.1 Hz, 1H), 7.45 (dt, J=9.0, 0.9 Hz, 1H), 7.67 (dd, J=8.9, 1.6Hz, 1H), 8.13 (dd, J=9.3, 1.2 Hz, 2H).

MS: [M+H]=460

Part II: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 2

Example 58: Synthesis of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)oxetan-3-ylmethylamide

1. Synthesis of Intermediate 58.1

2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol

A mixture of 4-ethylaniline (513 μl; 4.13 mmol), oxetane-3-carbaldehyde(807.3 mg; 3.75 mmol) and tetrahydrofuran (2.5 ml) is stirred for 2hours at room temperature. Sodium triacetoxyborohydride (1.19 g; 5.63mmol) is added and the reaction medium is stirred for 16 hours at roomtemperature, hydrolyzed and extracted with ethyl acetate.

The organic phases are combined, washed with brine, dried (Na₂SO₄) andconcentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol (340 mg; 40%) isobtained in the form of an orange oil with a ¹H NMR showing the openingof the oxetane.

MS: [M+H]=228

2. Synthesis of Intermediate 58.2

2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol

A mixture of 1H-indazole-5-sulfonyl chloride (368.5 mg; 1.62 mmol),pyridine (3.0 ml; 37.17 mmol) and (4-ethylphenyl)oxetan-3-ylmethylamine(340 mg; 1.78 mmol) is stirred for 30 minutes at a temperature of 100°C. under microwave irradiation.

The reaction medium is diluted with ethyl acetate. The organic phase iswashed with saturated ammonium chloride solution, with saturated sodiumhydrogen carbonate solution and with water. It is dried (MgSO₄),filtered and concentrated to dryness.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The1H-indazole-5-sulfonic acid(2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (260 mg; 39%) isobtained in the form of a colorless oil with a compliant ¹H NMR.

MS: [M+H]=408

3. Synthesis of Intermediate 58.3

1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide

A mixture of 1H-indazole-5-sulfonic acid(2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (1.26 g; 0.64mmol), cesium carbonate (0.31 mg; 0.96 mmol) and4-(bromomethyl)tetrahydropyran (100 μl; 0.76 mmol) inN-methyl-2-pyrrolidone (4 ml) is stirred for 1 hour at a temperature of80° C. The reaction medium is diluted with ethyl acetate (20 ml).

The organic phase is washed with saturated NH₄Cl solution, withsaturated NaHCO₃ solution and with water. The organic phase is dried(MgSO₄), filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 31%) isobtained in the form of a colorless oil. ¹H NMR (DMSO-d6) δ: 1.18 (t,J=7.6 Hz, 3H), 1.25-1.43 (m, 4H), 1.73 (p, J=6.4 Hz, 1H), 2.61 (q, J=7.6Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H), 3.35-3.41 (m, 1H), 3.46-3.52 (m,1H), 3.52-3.63 (m, 2H), 3.69 (qd, J=10.8, 4.9 Hz, 2H), 3.82 (ddd,J=11.4, 4.3, 2.2 Hz, 2H), 4.39 (d, J=7.0 Hz, 2H), 4.69 (t, J=5.1 Hz,1H), 6.95-7.02 (m, 2H), 7.16-7.22 (m, 2H), 7.44 (dd, J=9.0, 1.8 Hz, 1H),7.92 (d, J=8.9 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.31 (s, 1H)

MS: [M+H]=506

4. Synthesis of Compound 16 According to the Invention

60% sodium hydride (17.4 mg; 0.43 mmol) is added to a solution of1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 0.20 mmol)in tetrahydrofuran (3 ml). The reaction medium is stirred for 1 hour ata temperature of 80° C. and then for 16 hours at a temperature of 30° C.

The reaction medium is diluted with ethyl acetate (20 ml). The organicphase is washed with saturated NH₄Cl solution (20 ml), with saturatedNaHCO₃ solution (20 ml) and with water (20 ml). The organic phase isdried (MgSO₄), filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)oxetan-3-ylmethylamide (35.0 mg; 33%) is obtained in theform of a white solid.

¹H NMR (Methanol-d4) δ: 1.20 (t, J=7.6 Hz, 3H), 1.31-1.51 (m, 5H), 2.27(tq, J=10.6, 6.2, 5.6 Hz, 1H), 2.62 (q, J=7.6 Hz, 2H), 3.01 (hept, J=7.3Hz, 1H), 3.31-3.43 (m, 2H), 3.92 (d, J=7.7 Hz, 3H), 4.33-4.42 (m, 3H),4.56-4.66 (m, 2H), 6.88 (d, J=8.2 Hz, 2H), 6.93-7.03 (m, 1H), 7.13 (d,J=8.1 Hz, 2H), 7.58 (dd, J=8.9, 1.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H),8.13 (s, 1H)

MS: [M+H]=470

Part III: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 3

Example 59: Synthesis of methyl5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate

1. Synthesis of Intermediate 59.1

methyl 5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate

(4-Ethylphenyl)isobutylamine (417.5 mg; 2.35 mmol) is added to methyl5-chlorosulfonyl-1H-indazole-7-carboxylate (300 mg; 1.07 mmol) inacetonitrile (4 ml). The reaction medium is stirred for 1 hour 20minutes at a temperature of 100° C. under microwave irradiation.

The reaction medium is diluted with ethyl acetate, washed with 1Nhydrochloric acid solution, and then with saturated sodium hydrogencarbonate solution and with water, dried (MgSO₄), filtered andconcentrated.

The methyl5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate (429.8mg; 97%) is obtained in the form of a white solid with a compliant ¹HNMR.

MS: [M+H]=416

2. Synthesis of methyl5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate(compound 74)

4-(Bromomethyl)tetrahydropyran (97.6 μl; 0.74 mmol) is added to amixture of methyl5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate (280.0mg; 0.67 mmol) and cesium carbonate (329 mg; 1 mmol) in1-methyl-2-pyrrolidone (2.8 ml). The reaction medium is stirred at atemperature of 80° C. overnight.

The crude product is filtered and then purified by preparative HPLC (C18column, eluent: acetonitrile in water/0.1% of formic acid). The methyl5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate(223.4 mg; 63%) is obtained in the form of a white solid.

NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.25(dt, J=11.1, 5.3 Hz, 4H), 1.33-1.55 (m, 1H), 1.86-2.12 (m, 1H), 2.60 (q,J=7.6 Hz, 2H), 3.18 (td, J=11.1, 3.6 Hz, 2H), 3.35 (s, 2H), 3.79 (dt,J=11.4, 3.3 Hz, 2H), 3.93 (s, 3H), 4.57 (d, J=7.2 Hz, 2H), 6.93-7.06 (m,2H), 7.12-7.23 (m, 2H), 7.80 (d, J=1.7 Hz, 1H), 8.37 (d, J=1.9 Hz, 1H),8.48 (s, 1H)

MS: [M+H]=514

Example 60: Synthesis of5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylicacid amide

Aqueous ammonia (1.05 ml) is added to a solution of methyl5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylate(210.0 mg; 0.41 mmol) in N,N-dimethylformamide (1.05 ml).

The reaction medium is stirred for 3 days at room temperature and for 2days at a temperature of 60° C. The reaction medium is diluted andextracted with dichloromethane. The organic phases are combined, dried(MgSO₄), filtered and concentrated to dryness.

The crude product is filtered and then purified by preparative HPLC (C18column, eluent: acetonitrile in water/0.2% of ammonium carbonate). The5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-7-carboxylicamide is obtained in the form of a white solid.

¹H NMR (Chloroform-d) δ: 0.94 (d, J=6.7 Hz, 6H), 1.25 (t, J=7.6 Hz, 3H),1.38-1.51 (m, 4H), 1.59-1.69 (m, 1H), 2.08-2.21 (m, 1H), 2.67 (q, J=7.6Hz, 2H), 3.25-3.39 (m, 4H), 3.90-4.01 (m, 2H), 4.59 (d, J=7.2 Hz, 2H),5.75 (s, 1H), 6.00 (s, 1H), 6.94-7.00 (m, 2H), 7.11-7.18 (m, 2H), 7.62(d, J=1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.19 (s, 1H) MS: [M+H]=499

Part IV: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 4

Example 61: Synthesis ofN-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide

1. Synthesis of Intermediate 60.1

3-bromo-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide

N-Bromosuccinimide (120 mg; 0.67 mmol) is added to a solution of1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg; 0.56mmol) in dichloromethane (5 ml). The reaction medium is stirred for 16hours at room temperature, diluted with dichloromethane and extracted.

The organic phase is washed with saturated NH₄Cl solution, withsaturated NaHCO₃ solution and with water, dried (MgSO₄), filtered andconcentrated to dryness.

The 3-bromo-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide(260 mg; 100%) is obtained in the form of a pale yellow solid with acompliant ¹H NMR.

MS: [M+H]=436

2. Synthesis of Intermediate 60.2

3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide

A mixture of 3-bromo-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (260 mg; 0.60 mmol), cesium carbonate (388mg; 1.19 mmol) and 4-(bromomethyl)tetrahydropyran (160 mg; 0.89 mmol) inN-methyl-2-pyrrolidone (3 ml) is stirred for 1 hour at a temperature of80° C.

The reaction medium is diluted with ethyl acetate (30 ml). The organicphase is washed with saturated NH₄Cl solution (20 ml), with saturatedNaHCO₃ solution (20 ml) and with water (20 ml), dried (MgSO₄), filteredand concentrated to dryness.

The 3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (350 mg; 100%) is obtained in the form of aclear yellow oil with a compliant ¹H NMR.

MS: [M+H]=534

3. Synthesis of Compound 14 According to the Invention

2.5 M n-Butyllithium (900 μl; 2.24 mmol) is added, under argon, to asolution of3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (200 mg; 0.37 mmol) in tetrahydrofuran (3ml) at a temperature of −78° C. The reaction medium is stirred for 30minutes, paraformaldehyde (980 mg; 2.24 mmol) is then added, thetemperature is allowed to return to room temperature and the medium isthen stirred for 3 hours at a temperature of 60° C.

The reaction medium is hydrolyzed with 1M hydrochloric acid solution (5ml) at room temperature for 10 days, and diluted with ethyl acetate (50ml).

The organic phase is washed with saturated NH₄Cl solution (20 ml), withsaturated NaHCO₃ solution (20 ml) and with water (20 ml), dried (MgSO₄),filtered and concentrated to dryness.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The3-hydroxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonicacid (4-ethylphenyl)isobutylamide (20 mg; 11%) is obtained in the formof a colorless oil.

¹H NMR (CD3OD-d4) δ: 0.90 (d, J=6.7 Hz, 7H), 1.22 (t, J=7.6 Hz, 3H),1.27-1.58 (m, 4H), 1.71 (d, J=12.7 Hz, 2H), 2.16 (s, 1H), 2.64 (q, J=7.7Hz, 2H), 3.35 (s, 2H), 3.41 (t, J=11.6 Hz, 2H), 3.96 (dd, J=11.9, 4.1Hz, 2H), 4.66 (s, 2H), 6.92 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.9 Hz, 2H),7.16 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H)

MS: [M+H]=486

Part V: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 5

Example 62: Synthesis of 3-amino-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide

1. Synthesis of Intermediate 61.1

5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid

A solution of (4-ethylphenyl)isobutylamine (0.80 g; 4.51 mmol) andpyridine (0.36 ml; 4.51 mmol) in tetrahydrofuran (8 ml) is added to asolution of 5-chlorosulfonyl-2-fluorobenzoic acid (1.44 g; 5.87 mmol) intetrahydrofuran (8 ml).

The reaction medium is stirred for 19 hours at room temperature,hydrolyzed with aqueous 1N HCl solution and diluted with ethyl acetate.

The organic phase is washed with aqueous 1N HCl solution. The organicphase is dried (Na₂SO₄), filtered and concentrated.

The crude product is chromatographed on silica gel (eluent:dichloromethane/methanol, from 0 to 10% of methanol) and then bypreparative HPLC (C18 column, eluent: from 60% to 70% of acetonitrile inwater/0.1% of formic acid). The5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid (0.56 g; 33%)is obtained in the form of an off-white solid with a compliant ¹H NMR.

MS: [M−H]=378

2. Synthesis of Intermediate 61.2

5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic

A solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid(0.59 g; 1.55 mmol) in thionyl chloride (5.0 ml) is stirred for 3 hoursat reflux and then concentrated to dryness. The5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.62 g;100%) is obtained in the form of a brown oil.

MS: [M−H]=397

3. Synthesis of Intermediate 61.3

5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide

A 0.5M solution of ammonia in dioxane (8.4 ml; 4.2 mmol) is addedportionwise over a period of 43 hours to a solution of5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.31 g;0.78 mmol) in tetrahydrofuran (3 ml). The reaction medium is hydrolyzedwith aqueous NaHCO₃ solution and extracted with ethyl acetate.

The extracted organic phase is washed with 1N sodium hydroxide, dried(Na₂SO₄), filtered and concentrated. The crude product ischromatographed on silica gel (eluent: heptane/ethyl acetate, from 20 to50% of ethyl acetate). The5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g; 58%) isobtained in the form of a white solid with a compliant ¹H NMR.

MS: [M−H]=379

4. Synthesis of Intermediate 61.4

3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide

Triethylamine (0.19 ml; 1.35 mmol) and then trifluoroacetic anhydride(93 μl; 0.67 mmol) are added to a solution of5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g; 0.45mmol) at 0° C. The reaction medium is stirred for 1 hour, hydrolyzed for15 minutes and extracted with ethyl acetate. The organic phases arecombined, dried (Na₂SO₄), filtered and concentrated.

The 3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide(0.17 g; 89%) is obtained in the form of a white solid (HPLC purity=85%)with a compliant ¹H NMR.

MS: [M−H]=361

5. Synthesis of Compound 34 According to the Invention

Hydrazine hydrate (1.25 ml; 25.7 mmol) is added to a suspension of3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (0.19 g;0.45 mmol) in ethanol (2.5 ml). The reaction medium is stirred for 50minutes at a temperature of 100° C. in a tube. The reaction medium isconcentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.2% of ammonium carbonate). The3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (78 mg;53%) is obtained in the form of a solid.

¹H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.5 Hz, 3H),1.34-1.48 (m, 1H), 2.59 (q, J=7.7 Hz, 2H), 3.28-3.32 (m, 2H), 5.73 (s,2H), 6.96 (d, J=7.8 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.26 (d, J=8.8 Hz,1H), 7.32 (d, J=8.8 Hz, 1H), 8.19 (s, 1H), 11.91 (s, 1H).

MS: [M−H]=373

Example 63: Synthesis of 3-amino-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide

3-Amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (54 mg;0.14 mmol) in dimethyl sulfoxide (0.80 ml) is added to potassiumhydroxide (29 mg; 0.44 mmol) at 85% in dimethyl sulfoxide (0.20 ml). Thereaction medium is stirred for 5 minutes and4-(bromomethyl)tetrahydropyran (27 mg; 0.15 mmol) in dimethyl sulfoxide(0.50 ml) is then added. Stirring is continued for 3 hours 20 minutes,followed by hydrolysis with a few drops of water and filtration througha filter syringe. The filtrate is purified by preparative HPLC (C18column, eluent: acetonitrile in water/0.1% of formic acid).

The 3-amino-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid(4-ethylphenyl)isobutylamide (30 mg; 44%) is obtained in the form of acolorless oil.

¹H NMR (DMSO-d6) δ: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H),1.21-1.47 (m, 5H), 2.59 (q, J=7.6 Hz, 2H), 3.23 (td, J=11.5, 2.4 Hz,2H), 3.77-3.88 (m, 2H), 4.03 (d, J=7.0 Hz, 2H), 6.92-7.01 (m, 2H), 7.16(d, J=8.3 Hz, 2H), 7.26 (dd, J=8.9, 1.8 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H),8.17 (d, J=1.7 Hz, 1H).

MS: [M−H]=471

Part VI: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 6

Example 64: Synthesis of3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

1. Synthesis of Intermediate 63.1

1H-Indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

A mixture of 1H-indazole-6-sulfonyl chloride (500 mg; 2.31 mmol),pyridine (3 ml) and (4-ethylphenyl)oxetan-3-ylmethylamine (491 mg; 2.77mmol) is stirred for 30 minutes at a temperature of 50° C. The reactionmedium is diluted with ethyl acetate.

The organic phase is washed with saturated NH₄Cl solution, withsaturated NaHCO₃ solution and with water. It is dried over magnesiumsulfate, filtered and concentrated to dryness.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The1H-Indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (640 mg; 78%)is obtained in the form of a colorless oil and is obtained with acompliant ¹H NMR.

MS: [M+H]=358

2. Synthesis of Intermediate 63.2

3-bromo-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide

N-Bromosuccinimide (956 mg; 5.37 mmol) is added to a solution of1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (1.60 g; 4.48mmol) in dichloromethane (10 ml). The reaction medium is stirred for 16hours at room temperature and diluted with dichloromethane.

The organic phase is extracted and washed with saturated ammoniumchloride solution, with saturated sodium hydrogen carbonate solution andwith water. It is dried (MgSO₄), filtered and concentrated to dryness.The 3-bromo-1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide(1.9 g; 97%) is obtained in the form of a pale yellow solid with acompliant ¹H NMR.

MS: [M+H]=436

3. Synthesis of Intermediate 63.3

3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

A mixture of 3-bromo-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (700 mg; 1.60 mmol), pyridiniump-toluenesulfonate (202 mg; 0.80 mmol) and 3,4-dihydro-2H-pyran (0.58ml; 6.42 mmol) in tetrahydrofuran (10 ml) is stirred for 16 hours at 80°C. The reaction medium is diluted with ethyl acetate (20 ml) andextracted.

The organic phase is washed with saturated NH₄Cl solution, withsaturated NaHCO₃ solution and with water, dried (MgSO₄), filtered andconcentrated to dryness.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (500 mg; 57%) is obtained in the form of awhite solid.

¹H NMR (DMSO-d6) δ: 0.86 (dd, J=13.3, 6.7 Hz, 6H), 1.18 (t, J=7.6 Hz,3H), 1.38-1.63 (m, 3H), 1.68-1.81 (m, 1H), 1.98 (d, J=10.7 Hz, 2H), 2.60(q, J=7.6 Hz, 2H), 3.36-3.41 (m, 2H), 3.67-3.76 (m, 1H), 6.00 (dd,J=9.3, 2.4 Hz, 1H), 6.95-7.02 (m, 2H), 7.16-7.21 (m, 2H), 7.41 (dd,J=8.5, 1.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.99 (s, 1H)

MS: [M+H]=520

4. Synthesis of Intermediate 63.4

1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide

A mixture of p-toluenesulfonyl hydrazide (286 mg; 1.54 mmol),4-formyltetrahydropyran (175 mg; 1.54 mmol) and 1,4-dioxane (2 ml) isstirred for 1 hour under argon. Lithium tert-butoxide (125 mg; 1.54mmol), X-PHOS (18 mg; 0.04 mmol),tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (40 mg; 0.04mmol) and 3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (200 mg; 0.38 mmol) are added under argon,and the reaction medium is stirred for 5 hours at 100° C.

The reaction medium is diluted with 20 ml of ethyl acetate andextracted. The organic phase is washed with saturated NH₄Cl solution (20ml), with saturated NaHCO₃ solution (20 ml) and with water (20 ml),dried (MgSO₄), filtered and concentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 100% of ethyl acetate).

The1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (100 mg; 48%) is obtained in the formof a yellow oil with a compliant ¹H NMR.

MS: [M+H]=538

5. Synthesis of Compound 62 According to the Invention

A mixture of1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (100 mg; 0.19 mmol), acetic acid (6ml) and water (2 ml) is stirred for 5 hours at a temperature of 80° C.The reaction medium is diluted with 20 ml of ethyl acetate andextracted. The organic phase is washed with saturated NH₄Cl solution (20ml), with saturated NaHCO₃ solution (20 ml) and with water (20 ml),dried (MgSO₄), filtered and concentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (80 mg; 93%) is obtained in the form of awhite solid.

¹H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 7H), 1.17 (t, J=7.6 Hz, 3H), 1.41(dt, J=13.6, 6.8 Hz, 1H), 2.60 (q, J=7.3 Hz, 2H), 2.93 (t, J=5.4 Hz,2H), 3.65 (t, J=5.5 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 6.61 (s, 1H), 6.95(d, J=8.3 Hz, 2H), 7.13-7.21 (m, 2H), 7.22 (dd, J=8.5, 1.5 Hz, 1H),7.63-7.67 (m, 1H), 7.98 (d, J=8.5 Hz, 1H).

MS: [M+H]=454

Example 65: Synthesis of3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

3-(Tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (60 mg; 0.13 mmol) in methanol (3 ml) inthe presence of palladium (5% Pd on activated charcoal: Degussa type)(14 mg) is placed for 16 hours under hydrogen (1 atm). The reactionmedium is filtered through Celite. The filtrate is concentrated todryness. The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (30 mg; 50%) is obtained in the form of awhite solid.

¹H NMR (DMSO-d6) δ: 0.85 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.6 Hz, 3H),1.23-1.48 (m, 3H), 1.56 (d, J=13.4 Hz, 2H), 1.97 (d, J=11.7 Hz, 1H),2.56-2.65 (m, 2H), 2.90 (d, J=7.0 Hz, 2H), 3.26 (t, J=11.3 Hz, 2H), 3.82(dd, J=11.6, 3.8 Hz, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.19 (dd, J=14.2, 8.2Hz, 3H), 7.62 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 13.15 (s, 1H).

MS: [M+H]=456

Part VII: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme 7

Example 65: Synthesis of 3-morpholin-4-ylmethyl-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide

1. Synthesis of Intermediate 65.1

1-(tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

Bis(tri-t-butylphosphine)palladium(0) (49 mg; 0.10 mmol) is added to amixture, degassed under argon, of3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (500 mg; 0.96 mmol), cesium carbonate (940mg; 2.88 mmol) and vinylboronic anhydride-pyridine complex (462 mg; 1.92mmol) in 1,4-dioxane (3 ml) and water (1 ml).

The reaction medium is stirred for 3 hours at a temperature of 90° C.and filtered through Celite. The filtrate is diluted with ethyl acetateand extracted.

The organic phase is washed with 20 ml of saturated sodium hydrogencarbonate solution and with 20 ml of water. The organic phase is washedwith saturated NH₄Cl solution (20 ml), with saturated NaHCO₃ solution(20 ml) and with water (20 ml), dried (MgSO₄), filtered andconcentrated.

The crude product is chromatographed on silica gel (eluent:heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The1-(tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (400 mg; 89%) is obtained in the form of abeige-colored solid with a compliant ¹H NMR.

MS: [M+H]=468

2. Synthesis of Intermediate 65.2

3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide

1-(Tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (400 mg; 0.86 mmol) is added to a mixtureof (DHQ)₂PHAL (1.20 g; 1.46 mmol), tert-butyl alcohol (10 ml) and water(10 ml) cooled to a temperature of 0° C. The reaction medium is stirredfor 16 hours at a temperature of 40° C. Sodium sulfite (5 g) is added.

The reaction medium is stirred for 45 minutes, diluted with ethylacetate (30 ml) and extracted. The organic phases are combined, washedwith saturated Na₂SO₃ solution (20 ml) and with water (20 ml), dried(MgSO₄), filtered and concentrated. The crude product is chromatographedon silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethylacetate).

The3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (380 mg; 89%) is obtained in the formof a clear oil with a compliant ¹H NMR.

MS: [M+H]=502

3. Synthesis of Intermediate 65.3

3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

Sodium metaperiodate (1.62 g; 7.58 mmol) is added to a mixture of3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (380 mg; 0.76 mmol), acetone (2 ml),tetrahydrofuran (2 ml) and water (2 ml).

The reaction medium is stirred for 2 hours 30 minutes at a temperatureof 35° C., diluted with ethyl acetate (30 ml) and water (20 ml) andextracted.

The organic phases are combined, washed with saturated Na₂SO₃ solution(20 ml) and with water (20 ml), dried (MgSO₄), filtered andconcentrated. The3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (120 mg; 34%) is obtained in the form of awhite solid with a compliant ¹H NMR.

MS: [M+H]=470

4. Synthesis of Intermediate 65.4

3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide

Morpholine (45 μl; 0.51 mmol) and sodium triacetoxyborohydride (119 mg;0.56 mmol) are added to a solution of3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (120 mg; 0.26 mmol) in tetrahydrofuran (3ml). The reaction medium is stirred for 2 hours at room temperature. Thereaction medium is diluted with ethyl acetate (20 ml) and water (10 ml)and extracted.

The organic phase is washed with saturated NH₄Cl solution (20 ml), withsaturated NaHCO₃ solution (20 ml) and with water (20 ml), dried (MgSO₄)and concentrated.

The3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (130 mg; 94%) is obtained in the formof an oil with a compliant ¹H NMR.

MS: [M+H]=541

5. Synthesis of Compound 64 According to the Invention

A mixture of3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (130 mg; 0.24 mmol), acetic acid (30ml) and water (10 ml) and a few drops of trifluoroacetic acid is stirredfor 4 days at a temperature of 80° C. The reaction medium is dilutedwith 50 ml of ethyl acetate and extracted.

The organic phase is washed with saturated NH₄Cl solution (20 ml), withsaturated NaHCO₃ solution (20 ml) and with water (20 ml), dried (MgSO₄),filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The3-morpholin-4-ylmethyl-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (70 mg; 64%) is obtained in the form of awhite solid after recrystallization from an acetone/water mixture.

1H NMR (DMSO-d6) δ: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 2.44(t, J=4.5 Hz, 4H), 2.61 (t, J=7.6 Hz, 2H), 3.33-3.37 (m, 2H), 3.87 (s,2H), 6.95-7.00 (m, 2H), 7.15-7.21 (m, 2H), 7.25 (dd, J=8.5, 1.5 Hz, 1H),8.06 (d, J=8.5 Hz, 1H), 13.27 (s, 1H).

MS: [M+H]=457

Example 66: Synthesis of3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

1. Synthesis of Intermediate 66.1

3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide

cis-2,6-Dimethylmorpholine (50 μl; 0.38 mmol) and sodiumtriacetoxyborohydride (122 mg; 0.57 mmol) are added to a solution of3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (90 mg; 0.19 mmol) in tetrahydrofuran (2ml).

The reaction medium is stirred for 16 hours at room temperature. Thereaction medium is diluted with ethyl acetate (20 ml) and water (10 ml)and extracted. The organic phase is washed with saturated NH₄Cl solution(20 ml), with saturated NaHCO₃ solution (20 ml) and with water (20 ml),dried (MgSO₄) and concentrated. The3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (90 mg; 83%) is obtained in the formof an oil with a compliant ¹H NMR.

MS: [M+H]=570

2. Synthesis of Compound 65 According to the Invention

A mixture of3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (90 mg; 0.16 mmol), acetic acid (10ml) and water (10 ml) and one drop of trifluoroacetic acid is stirredfor 16 hours at a temperature of 80° C. The reaction medium is dilutedwith 50 ml of ethyl acetate and extracted.

The organic phase is washed with saturated NH₄Cl solution (20 ml), withsaturated NaHCO₃ solution (20 ml) and with water (20 ml), dried (MgSO₄),filtered and concentrated.

The crude product is purified by preparative HPLC (C18 column, eluent:acetonitrile in water/0.1% of formic acid). The3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (52 mg; 67%) is obtained in the form of acolorless oil.

1H NMR (DMSO-d6) δ: 0.85 (d, J=6.5 Hz, 6H), 1.02 (d, J=6.1 Hz, 6H), 1.18(t, J=7.5 Hz, 3H), 1.42 (dt, J=13.3, 7.1 Hz, 1H), 1.74 (t, J=10.7 Hz,2H), 2.55-2.65 (m, 2H), 2.70-2.80 (m, 2H), 3.33-3.44 (m, 2H), 3.55 (t,J=7.8 Hz, 2H), 3.85 (s, 2H), 6.98 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.3 Hz,2H), 7.23 (d, J=8.6 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.20(s, 1H), 13.25 (s, 1H).

MS: [M+H]=485

Example 67: Synthesis of3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide

1. Synthesis of Intermediate 67.1

3-((S)-3-methylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide

With a procedure similar to that described for intermediate 67.1,3-((S)-3-methylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonicacid (4-ethylphenyl)isobutylamide (90 mg; 85%) is obtained in the formof an oil with a compliant ¹H NMR.

MS: [M+H]=555

2. Synthesis of Compound 66 According to the Invention

With a procedure similar to that described for example 66,3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide (42 mg; 54%) is obtained in the form of acolorless oil.

1H NMR (DMSO-d6) δ: 0.86 (d, J=6.8 Hz, 6H), 1.09-1.22 (m, 7H), 1.42 (dt,J=13.9, 6.9 Hz, 1H), 2.16-2.27 (m, 1H), 2.61 (t, J=7.6 Hz, 2H), 3.38 (d,J=19.0 Hz, 5H), 3.58-3.72 (m, 3H), 6.98 (d, J=7.9 Hz, 2H), 7.18 (d,J=7.9 Hz, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 8.04 (d, J=8.6 Hz,1H), 8.24 (s, 1H), 13.24 (s, 1H).

MS: [M+H]=471

The invention claimed is:
 1. A compound of formula (II), or apharmaceutically acceptable salt thereof, a hydrate thereof, or asolvate thereof:

wherein: one or two of the elements Y¹, Y², Y³, Y⁴ and Y⁵ represent(s) anitrogen atom and the other elements correspond to a group —CR², or eachof the elements Y¹, Y², Y³, Y⁴ and Y⁵ corresponds to a group —CR², R¹represents a linear or branched C₃-C₅ alkyl radical, optionallysubstituted with a hydroxyl group and/or a halogen atom, a C₃-C₅cycloalkyl radical, a —CH₂—(C₃-C₅)cycloalkyl radical, or a—CH₂—(C₄-C₆)heterocycloalkyl radical, R² represents a hydrogen atom or ahalogen atom, a linear or branched C₁-C₅ alkyl radical, a C₁-C₄ alkoxyradical, a cyano group —CN, or a radical —C(═O)R′² with R′² denoting aC₁-C₃ alkoxy radical, or a —CF₃ radical; said alkyl, alkenyl and alkoxyradicals optionally being substituted with one or more halogen atoms, R³represents a hydrogen atom, a halogen atom, or a group(CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷ or a group CH═R⁷, n and o are zero, pis zero or 1, R′⁶ represent a hydrogen atom, R⁷ represents: aheterocycloalkyl radical, wherein the heterocycloalkyl radical isoptionally substituted with one or more halogen atoms, one or morelinear or branched C₁-C₃ alkyl groups, one or more —OH groups, one ormore carbonyl functions, one or more linear or branched C₁-C₄hydroxyalkyl groups, one or more amino groups, one or more groups—C(═O)R^(7a), or one or more groups S(═O)₂R^(7a); R^(7a) representing alinear or branched C₁-C₃ alkyl radical, a linear or branched C₁-C₃alkoxy radical, or an amino radical N(R^(8a))(R^(8b)), an aromaticradical, wherein the aromatic radical is optionally substituted with oneor more halogen atoms, one or more linear or branched C₁-C₃ alkyl groupsoptionally substituted with one or more halogen atoms, one or more C₁-C₃alkoxy groups, one or more amino groups —NR¹¹R¹², one or more groups—COR¹¹, one or more groups —COOR¹¹, one or more amido groups CONR¹¹R¹²,one or more groups —SOR¹¹, one or more groups —SO₂R¹¹, one or moregroups —NHCOR¹¹, one or more groups —NHCOOR¹¹, one or more groups—SO₂NR¹¹R¹² or one or more CN groups; R¹¹ and R¹², which are identicalor different, representing a hydrogen atom, a hydroxyl radical —OH, or alinear or branched C₁-C₃ alkyl radical optionally substituted with oneor more halogen atoms; or a heteroaromatic radical, wherein theheteroaromatic radical is optionally substituted with one or morehalogen atoms, one or more linear or branched C₁-C₃ alkyl groupsoptionally substituted with one or more halogen atoms, one or more C₁-C₃alkoxy groups, one or more amino groups —NR¹¹R¹², one or more groups—COR¹¹, one or more groups —COOR¹¹, one or more amido groups CONR¹¹R¹²,one or more groups —SOR¹¹, one or more groups —SO₂R¹¹, one or moregroups —NHCOR¹¹, one or more groups —NHCOOR¹¹, one or more groups—SO₂NR¹¹R¹² or one or more CN groups; R¹¹ and R¹², which are identicalor different, representing a hydrogen atom, a hydroxyl radical —OH, or alinear or branched C₁-C₃ alkyl radical optionally substituted with oneor more halogen atoms; R⁵ represents a hydrogen atom, a linear orbranched C₁-C₃ alkyl radical optionally substituted with one or morehalogen atoms; an amino radical —NH₂, an OCH₂—(C₄-C₅) heterocyclicradical, or a radical CH₂R′^(7a) with R′^(7a) denoting a hydroxyl group—OH function, and R^(8a) and R^(8b), which are identical or different,denote a hydrogen atom, a linear or branched C₁-C₃ alkyl radical or acyclopropyl radical.
 2. A compound of formula (III), or apharmaceutically acceptable salt thereof, a hydrate thereof, or asolvate thereof:

wherein: one or two of the elements Y¹, Y², Y³, Y⁴ and Y⁵ represent(s) anitrogen atom and the other elements correspond to a group —CR², or eachof the elements Y¹, Y², Y³, Y⁴ and Y⁵ corresponds to a group —CR², R¹represents a linear or branched C₃-C₅ alkyl radical, optionallysubstituted with a hydroxyl group and/or a halogen atom, a C₃-C₅cycloalkyl radical, a linear or branched C₂-C₅ alkenyl radical, a—CH₂—(C₃-C₅)cycloalkyl radical, a C₄-C₅ heterocycloalkyl radical, or a—CH₂—(C₄-C₆)heterocycloalkyl radical, R² represents a hydrogen atom or ahalogen atom, a linear or branched C₁-C₅ alkyl radical, a linear orbranched C₂-C₄ alkenyl radical, a C₁-C₄ alkoxy radical, a cyano group—CN, a radical —C(═O)R′² with R′² denoting a C₁-C₃ alkoxy radical, or a—CF₃ radical; said alkyl, alkenyl and alkoxy radicals optionally beingsubstituted with one or more halogen atoms, R³ represents a hydrogenatom, a halogen atom, a group (CHR⁶)_(n)—(Z)_(o)—(CHR′⁶)_(p)—R⁷ or agroup CH═R⁷, n, o and p, which are identical or different, representzero or a natural integer ranging from 1 to 3, Z represents a divalentgroup selected from the group consisting of a methylene group —CH₂—, anamino group —NH— and an oxygen atom —O—, R⁶ and R′⁶, which are identicalor different, represent a hydrogen atom, a methyl group —CH₃, a group—OH, a hydroxymethyl group, or a carboxylic function COOH, R⁷represents: a hydrogen or a halogen atom, a group COOR′⁷ with R′⁷denoting (C₁)alkyl(C₆)heterocycle, a heterocycloalkyl radical, whereinthe heterocycloalkyl radical is optionally substituted with one or morehalogen atoms, one or more linear or branched C₁-C₃ alkyl groups, one ormore —OH groups, one or more carbonyl functions, one or more linear orbranched C₁-C₄ hydroxyalkyl groups, one or more amino groups, one ormore groups —C(═O)R^(7a), or one or more groups S(═O)₂R^(7a); R^(7a)representing a linear or branched C₁-C₃ alkyl radical, a linear orbranched C₁-C₃ alkoxy radical, or an amino radical N(R^(8a))(R^(8b)), aC₃-C₆ cycloalkyl radical, wherein the cycloalkyl radical is optionallysubstituted with one or more methyl radicals, one or more halogen atoms,a cyano group —CN or one or more groups —COR¹³; R¹³ denoting a linear orbranched C₁-C₃ alkoxy radical, or a hydroxyl group, an aromatic radical,wherein the aromatic radical is optionally substituted with one or morehalogen atoms, one or more linear or branched C₁-C₃ alkyl groupsoptionally substituted with one or more halogen atoms, one or more C₁-C₃alkoxy groups, one or more amino groups —NR¹¹R¹², one or more groups—COR¹¹, one or more groups —COOR¹¹, one or more amido groups CONR¹², oneor more groups —SOR¹¹, one or more groups —SO₂R¹¹, one or more groups—NHCOR¹¹, one or more groups —NHCOOR¹¹, one or more groups —SO₂NR¹¹R¹²or one or more CN groups; R¹¹ and R¹², which are identical or different,representing a hydrogen atom, a hydroxyl radical —OH, or a linear orbranched C₁-C₃ alkyl radical optionally substituted with one or morehalogen atoms; or a heteroaromatic radical, wherein the heteroaromaticradical is optionally substituted with one or more halogen atoms, one ormore linear or branched C₁-C₃ alkyl groups optionally substituted withone or more halogen atoms, one or more C₁-C₃ alkoxy groups, one or moreamino groups —NR¹¹R¹², one or more groups —COR¹¹, one or more groups—COOR¹¹, one or more amido groups CONR¹¹R¹², one or more groups —SOR¹¹,one or more groups —SO₂R¹¹, one or more groups —NHCOR¹¹, one or moregroups —NHCOOR¹¹, one or more groups —SO₂NR¹¹R¹² or one or more CNgroups; R¹¹ and R¹², which are identical or different, representing ahydrogen atom, a hydroxyl radical —OH, a linear or branched C₁-C₃ alkylradical optionally substituted with one or more halogen atoms; R⁵represents a hydrogen atom, a linear or branched C₁-C₃ alkyl radicaloptionally substituted with one or more halogen atoms; an amino radical—NH₂, a C₄-C₅ heterocyclic radical, an OCH₂—(C₄-C₅) heterocyclicradical, a radical CH₂R′^(7a) with R′^(7a) denoting a methoxy radical, ahydroxyl group —OH, a —CH₂COOH group, a group —CH(R^(5b))OH, acarboxylic group —COOH, a —CN group, or a thioxo function, R^(5b)represents a hydrogen atom, a linear or branched C₁-C₃ alkyl radicaloptionally substituted with one or more carboxylic functions, or acyclopropyl radical, and R^(8a) and R^(8b), which are identical ordifferent, denote a hydrogen atom, a linear or branched C₁-C₃ alkylradical or a cyclopropyl radical.
 3. The compound of formula (II) asdefined by claim 1, wherein the compound is selected from the groupconsisting of: 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonicacid (4 ethylphenyl)(1 ethylpropyl)amide Compound 1,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid ((R)-sec-butyl)(4-ethylphenyl)amide Compound 2,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acidcyclopropyl(4-ethylphenyl)amide Compound 3,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(tetrahydropyran-4- ylmethyl)amide Compound 5,

1-((3,5-dimethylisoxazol-4- yl)methyl)-N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide Compound 6,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-isopropylphenyl)amide Compound 7,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)propyl Compound 8,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid butyl(4-ethylphenyl)amide Compound 9,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-chloro-2-fluorophenyl)isobutylamide Compound 10,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5-dimethylphenyl)isobutylamide Compound 11,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-methoxypyridin-2-yl)isobutylamide Compound 12,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-butyl-2-methylphenyl)isobutylamide Compound 13,

N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide Compound 14,

3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamideCompound 15,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)oxetan-3-ylmethylamide Compound 16,

1-(1-acetylpyrrolidin-3-yl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 17,

3-(tetrahydropyran-4-ylmethoxy)-1- (tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid (4- ehtlyphenyl)isobutylamide Compound 18,

1-(3,5-dimethylisoxazol-4-ylmethyl)- 1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 19,

1-((1-acetylpyrrolidin-3-yl)methyl)-N- (4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide Compound 20,

N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydrofuran-3-yl)methyl)-1H-indazole-5-sulfonamide Compound 21,

N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydro-2H-pyran-3-yl)methyl)-1H-indazole-5-sulfonamide Compound 22,

1-benzyl-N-(4-ethylphenyl)-N- isobutyl-1H-indazole-5-sulfonamideCompound 23,

N-(cyclobutylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5- sulfonamide Compound 24,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-methoxyphenyl)isobutylamide Compound 25,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-methylphenyl)isobutylamide Compound 26,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4-dimethylphenyl)isobutylamide Compound 27,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3,5-dimethylphenyl)isobutylamide Compound 28,

N-(4-ethylphenyl)-N-isopropyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide Compound 29,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid sec-butyl(4-ethylphenyl)amide Compound 30,

N-(cyclopropylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5- sulfonamide Compound 31,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acidcyclopentyl(4-ethylphenyl)amide Compound 32,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide Compound 33,

3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamideCompound 34,

N-(4-ethylphenyl)-N-isopentyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide Compound 35,

N-(4-ethylphenyl)-N-isobutyl-1- (pyridin-4-ylmethyl)-1H-indazole-5-sulfonamide Compound 36,

N-(4-ethylphenyl)-N-isopentyl-1- (oxetan-3-ylmethyl)-1H-indazole-5-sulfonamide Compound 37

1-(tetrahydropyran-4-yl)-1H-indazole- 5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 38,

N-(4-ethylphenyl)-N-isopentyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulfonamide Compound 39,

1-(1-acetylpyrrolidin-3-yl)-1H- indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 40,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acidcyclobutyl(4- ethylphenyl)amide Compound 41,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-fluoro-2-methylphenyl)isobutylamide Compound 42,

1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid (3-fluoro-2-methylphenyl)isobutylamide Compound 43,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-chlorophenyl)isobutylamide Compound 44,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide Compound 45,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-fluorophenyl)isobutylamide Compound 46,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-p-tolylamide Compound 47,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-o-tolylamide Compound 48,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-trifluoromethoxyphenyl) isobutylamide Compound 49,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(5-isopropylpyridin-2-yl)amide Compound 50,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-chloro-benzyl)isobutylamide Compound 51,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(2-trifluoromethylbenzyl)amide Compound 52,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide Compound 53,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-fluoro-2-methylphenyl)isobutylamide Compound 54,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(4-methoxy-2-methylphenyl)amide Compound 55,

methyl 4-{isobutyl[1- (tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonyl]amino}-3- methylbenzoate Compound 56,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-cyano-2-methylphenyl)isobutylamide Compound 57,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(2-trifluoromethylphenyl)amide Compound 58,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl(4-trifluoromethylphenyl)amide Compound 59,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-chloro-2-hydroxymethylpropyl)(4- ethylphenyl)amide Compound 60,

3-(tetrahydropyran-4-ylmethoxy)-1H- indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide Compound 61,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid isobutyl-o-tolylamide Compound 69,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-cyano-4-methylphenyl)isobutylamide Compound 70,

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)isobutylamide Compound 71, and

1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)isobutylamide Compound
 73.


4. A pharmaceutical composition comprising at least one compound offormula (II) according to claim 1, or a pharmaceutically acceptable saltthereof, a hydrate thereof, or a solvate thereof.
 5. The pharmaceuticalcomposition as defined by claim 4, wherein the composition is formulatedfor topical or oral administration.
 6. The pharmaceutical composition asdefined by claim 4, wherein the composition is formulated for treatingacne, atopic dermatitis and/or psoriasis.
 7. The pharmaceuticalcomposition as defined by claim 5, wherein the composition is formulatedfor oral administration in the form of a table, a gel capsule, a coatedtablet, a syrup, a suspension, a solution, a powder, a granule, anemulsion, a suspension comprising a microsphere, a suspension comprisinga nanosphere, a lipid vesical, or a polymeric vesicle.
 8. Thepharmaceutical composition as defined by claim 5, wherein thecomposition is formulated for topical administration in the form of anointment, a cream, a milk, a pomade, a powder, an impregnated pad, asyndet, a solution, a gel, a spray, a mousse, a suspension, a stick, ashampoo, or a washing base.
 9. The compound of formula (II) as definedby claim 1, wherein R⁷ represents a heterocyclic radical selected fromthe group consisting of:

in which: R^(7a) represents a linear or branched C₁-C₃ alkyl radical,and R⁸ and R⁹ represent a hydrogen atom.
 10. The compound of formula(II) as defined by claim 1, wherein R⁷ represents an aromatic orheteroaromatic radical selected from the group consisting of:

in which: R₁₀ represents a hydrogen atom or a linear or branched C₁-C₃alkyl group, and m denotes zero or a natural integer ranging from 1 to3.
 11. The compound of formula (III) as defined by claim 2, wherein R⁷represents a heterocyclic radical selected from the group consisting of:

in which: R^(7a) represents a linear or branched C₁-C₃ alkyl radical, alinear or branched C₁-C₃ alkoxy radical or an amino radicalN(R^(8a))(R^(8b)), R^(8a) and R^(8b), which may be identical ordifferent, denote a hydrogen atom, a linear or branched C₁-C₃ alkylradical or a cyclopropyl radical, R₈ and R₉, which are identical ordifferent, represent a hydrogen atom, a linear or branched C₁-C₃ alkylradical, a hydroxyl group —OH, a carbonyl function ═O, a C₁ hydroxyalkylradical (—CH₂OH), or an amino group NH₂, and R₈ and R₉ can form,together with the carbon atoms to which they are attached, a 5- to7-membered carbocyclic ring.
 12. The compound of formula (III) asdefined by claim 2, wherein R⁷ represents an aromatic or heteroaromaticradical selected from the group consisting of:

in which: R₁₀ represents a hydrogen atom or a halogen atom, one linearor branched C₁-C₃ alkyl group optionally substituted with one or morehalogen atoms, one C₁-C₃ alkoxy group, one amino group —NR¹¹R¹², onegroup —COR¹¹, one group —COOR¹¹, one amido group —CONR¹¹R¹², one group—SOR¹¹, one group —SO₂R¹¹, one group —NHCOR¹¹, one group —NHCOOR¹¹, onegroup —SO₂NR¹¹R¹² or one —CN group; R¹¹ and R¹², which are identical ordifferent, representing a hydrogen atom or a linear or branched C₁-C₃alkyl radical optionally substituted with one or more halogen atoms, andm denotes zero or a natural integer ranging from 1 to
 3. 13. Thecompound of formula (III) as defined by claim 2, wherein the compound isselected from the group consisting of:

3-bromo-1-(tetrahydropyran-2-yl)-1H- indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 4,

3-(tetrahydropyran-4-ylidenemethyl)- 1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 62,

3-(tetrahydropyran-4-ylmethyl)-1H- indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 63,

3-morpholin-4-ylmethyl-1H-indazole- 6-sulfonic acid (4-ethylphenyl)isobutylamide Compound 64,

3-((cis)-2,6-dimethylmorpholin-4- ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide Compound 65, and

3-((S)-3-methylmorpholin-4- ylmethyl)-1H-indazole-6-sulfonic acid(4-ethylphenyl)isobutylamide Compound
 66.


14. A pharmaceutical composition comprising at least one compound offormula (III) according to claim 2, or a pharmaceutically acceptablesalt thereof, a hydrate thereof, or a solvate thereof.
 15. Thepharmaceutical composition as defined by claim 14, wherein thecomposition is formulated for topical or oral administration.
 16. Thepharmaceutical composition as defined by claim 14, wherein thecomposition is formulated for treating acne, atopic dermatitis and/orpsoriasis.
 17. The pharmaceutical composition as defined by claim 15,wherein the composition is formulated for oral administration in theform of a table, a gel capsule, a coated tablet, a syrup, a suspension,a solution, a powder, a granule, an emulsion, a suspension comprising amicrosphere, a suspension comprising a nanosphere, a lipid vesical, or apolymeric vesicle.
 18. The pharmaceutical composition as defined byclaim 15, wherein the composition is formulated for topicaladministration in the form of an ointment, a cream, a milk, a pomade, apowder, an impregnated pad, a syndet, a solution, a gel, a spray, amousse, a suspension, a stick, a shampoo, or a washing base.
 19. Acompound selected from the group consisting of: